View source for Cytochrome P450/ja

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'''シトクロムP450'''（'''P450s'''または'''CYPs'''）は、[[heme/ja|ヘム]]を[[cofactor (biochemistry)/ja|補因子]]として含む[[enzyme/ja|酵素]]の[[Protein superfamily/ja|スーパーファミリー]]の一つであり、そのほとんどが[[monooxygenase/ja|モノオキシゲナーゼ]]として機能するが、それだけに限定されるわけではない。哺乳類では、これらのタンパク質は[[steroid/ja|ステロイド]]類、[[fatty acid/ja|脂肪酸]]類、[[xenobiotic/ja|異種物質]]類を酸化し、様々な化合物の[[clearance (pharmacology)/ja|クリアランス]]、ホルモン合成と分解、ステロイドホルモン合成、薬物代謝、[[secondary metabolite/ja|防御化合物]]、脂肪酸、ホルモンの生合成に重要である。CYP450酵素はゼノバイオティクスを親水性の誘導体に変換し、排泄されやすくする。触媒する変換のほとんどすべてにおいて、P450は[[hydroxylation/ja|ヒドロキシル化]]に影響を及ぼす。

P450酵素は、[[animal/ja|動物]]、[[plant/ja|植物]]、[[fungus/ja|菌類]]、[[protist/ja|原生生物]]、[[bacteria/ja|細菌]]、[[archaea/ja|古細菌]]、および[[virus/ja|ウイルス]]のすべての[[kingdom (biology)/ja|界]]で同定されている。例えば、''[[Escherichia coli/ja|大腸菌]]''では見つかっていない。2018年現在、30万以上の異なるCYPタンパク質が知られている。

P450は一般に[[electron transfer/ja|電子伝達]]鎖の末端酸化酵素であり、大別すると[[P450-containing systems/ja|P450含有系]]となる。"P450"という用語は、酵素が[[redox/ja|酸化還元]]状態で[[carbon monoxide/ja|一酸化炭素]]と複合体化したときの[[absorption spectroscopy/ja|吸収極大]]の[[spectrophotometry/ja|分光光度]][[:en:wavelength|波長]]（450&nbsp;[[:en:nanometre|nm]]）にあるピークに由来する。ほとんどのP450は、[[iron/ja|鉄]]（そして最終的には分子状の[[oxygen/ja|酸素]]）を還元するために1つ以上の[[electron/ja|電子]]を供給するタンパク質パートナーを必要とする。

==命名法==
{{Anchor|Nomenclature}}
P450酵素をコードする[[Gene/ja|遺伝子]]および酵素自体は、[[protein superfamily/ja|スーパーファミリー]]を表す[[gene nomenclature/ja#Symbol and name|ルート記号]]'''CYP'''の後に、[[gene family/ja|遺伝子ファミリー]]を表す数字、サブファミリーを表す大文字、個々の遺伝子を表す別の数字が続く。遺伝子に言及する際には''[[:en:Italic type|イタリック体]]''で表記するのが慣例である。例えば、''CYP2E1'' は[[paracetamol/ja|パラセタモール]]（アセトアミノフェン）の代謝に関与する酵素の一つである[[CYP2E1/ja|CYP2E1]]をコードする遺伝子である。''CYP''命名法は公式の命名規則であるが、'''CYP450'''または'''CYP<sub>450</sub>'''が同義語として用いられることもある。これらの名称は、命名規則に従って（ファミリー番号450のP450を示すため）決して使用すべきではない。しかし、P450の遺伝子名や酵素名の中には、歴史的な名称（例えば、CYP102A1のP450<sub>BM3</sub>）や、触媒活性や基質として使用される化合物の名称を示す機能名で呼ばれるものもある。例えば、[[CYP5A1/ja|CYP5A1]]、[[thromboxane/ja|トロンボキサン]]A<sub>2</sub>合成, [[Thromboxane-A synthase/ja|TBXAS1]]（'''T'''hrom'''B'''o'''X'''ane '''A'''<sub>2</sub> '''S'''ynthase '''1'''）、[[CYP51A1/ja|CYP51A1]], ラノステロール14-α-デメチラーゼ、基質（'''L'''anosterol）と活性（'''D'''e'''M'''ethylation）により、非公式にLDMと略されることもある。

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現在の命名法ガイドラインでは、新しいCYPファミリーのメンバーは少なくとも40%の[[amino acid/ja|アミノ酸]]同一性を共有し、サブファミリーのメンバーは少なくとも55%のアミノ酸同一性を共有することが推奨されている。命名法委員会は、基本遺伝子名（[http://drnelson.uthsc.edu/CytochromeP450.html Cytochrome P450 Homepage] {{Webarchive|url=https://web.archive.org/web/20100627184446/http://drnelson.uthsc.edu/CytochromeP450.html |date=2010-06-27 }}）と[[allele/ja|対立遺伝子]]名（[https://www.pharmvar.org// CYP Allele Nomenclature Committee])の両方を割り当て、追跡している。
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== 分類 ==
{{Anchor|Classification}}
{{Main/ja|P450-containing systems/ja}}
電子伝達タンパク質の性質に基づき、P450はいくつかのグループに分類される：

;ミクロソームP450系：電子が[[nicotinamide adenine dinucleotide phosphate/ja|NADPH]]から[[cytochrome P450 reductase/ja|シトクロムP450還元酵素]]（CPR、POR、CYPORなど様々）を介して移動する。[[Cytochrome b5/ja|シトクロムb<sub>5</sub>]]（cyb<sub>5</sub>）もまた、[[cytochrome b5 reductase/ja|シトクロムb<sub>5</sub>レダクターゼ]]（CYB<sub>5</sub>R）によって還元された後、この系に還元力を寄与することができる。
;ミトコンドリアP450システム：NADPHからP450に電子を移動させるために[[adrenodoxin reductase/ja|アドレノドキシン還元酵素]]と[[adrenodoxin/ja|アドレノドキシン]]を用いる。
;バクテリアP450システム：P450に電子を伝達するために[[ferredoxin reductase/ja|フェレドキシン還元酵素]]と[[ferredoxin/ja|フェレドキシン]]を用いる。
;CYB<sub>5</sub>R/cyb<sub>5</sub>/P450系：CYPが必要とする両方の電子がシトクロムb<sub>5</sub>から来る。
;FMN/Fd/P450システム：もともとは''[[Rhodococcus/ja|ロドコッカス]]''属で発見されたもので、[[flavin mononucleotide/ja|FMN]]ドメインを含む[[reductase/ja|還元酵素]]がCYPに融合している。
;P450系のみ：外部からの還元力を必要としない。代表的なものに[[thromboxane synthase/ja|トロンボキサン合成酵素]]（CYP5）、[[prostacyclin synthase/ja|プロスタサイクリン合成酵素]]（CYP8）、CYP74A（[[allene oxide synthase/ja|アレンオキシド合成酵素]]）がある。

シトクロムP450が触媒する最も一般的な反応はモノオキシゲナーゼ反応であり、例えば、有機基質（RH）の脂肪族位に酸素の1原子を挿入し、もう1つの酸素原子は[[redox/ja|還元]]されて水になる：
{{center|1=
RH + O<sub>2</sub> + NADPH + H<sup>+</sup> → ROH + H<sub>2</sub>O + NADP<sup>+</sup> 
}} 多くの[[hydroxylation/ja|水酸化]]反応（[[hydroxyl/ja|水酸基]]の挿入）にはCYP酵素が使われる。

==メカニズム==
{{Anchor|Mechanism}}
[[Image:P450cycle.svg|alt=P450触媒サイクル|thumb|400px|左下の「Fe(V)中間体」は単純化したもので、[[noninnocent ligand/ja|ラジカルヘム配位子]]を持つFe(IV)である。]]

=== 構造 ===
シトクロムP450の活性部位にはヘム鉄中心がある。鉄は[[cysteine/ja|システイン]][[thiolate/ja|チオラート]][[ligand/ja|リガンド]]を介してタンパク質に結合している。このシステインといくつかの隣接残基は、既知のP450において高度に保存されており、正式な[[PROSITE/ja|PROSITE]]シグネチャーコンセンサスパターン[FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - <u>C</u> - [LIVMFAP] - [GAD]を持っている。P450によって触媒される反応は多種多様であるため、多くのP450の活性と特性は多くの点で異なっている。一般的に、P450の触媒サイクルは以下のように進行する：

===触媒サイクル===
# 基質は[[heme group/ja|ヘム基]]に近接し、チオラート軸とは反対側に結合する。 基質が結合すると、活性部位のコンフォメーションが変化し、多くの場合、水分子がヘム鉄の遠位軸配位位置からはずれ、ヘム鉄の状態が低スピンから高スピンへと変化する。
# 基質が結合すると、NAD(P)Hから[[cytochrome P450 reductase/ja|シトクロムP450還元酵素]]または関連する別の[[reductase/ja|還元酵素]]を介して電子移動が起こる。
# 分子状酸素は、結果として生じる第一鉄ヘム中心に遠位軸配位で結合し、最初はオキシミオグロビンに似た[[transition metal dioxygen complex/ja|酸素付加体]]を与える。
# 第2の電子は、[[cytochrome P450 reductase/ja|シトクロムP450還元酵素]]、[[ferredoxin/ja|フェレドキシン]]、[[cytochrome b5/ja||シトクロムb<sub>5</sub>]]のいずれかから移動し、Fe-O<sub>2</sub>付加体を還元して短命のペルオキソ状態を与える。
# ステップ4で形成されたペルオキソ基は急速に2回プロトン化され、1分子の水を放出し、'''P450化合物1'''（または単に化合物I）と呼ばれる高反応性種を形成する。 この反応性の高い中間体は2010年に単離され、P450化合物1は、[[porphyrin/ja|ポルフィリン]]とチオラート配位子上にさらに酸化当量が[[delocalized/ja|非局在化]]した鉄(IV)オキソ（または[[ferryl/ja|フェリル]]）種である。代替的なフェリル[[high-valent iron/ja|鉄(V)-オキソ]]の証拠は不足している。
# 関与する基質と酵素に応じて、P450酵素は多種多様な反応のいずれかを触媒することができる。 この図に、仮定の水酸化反応を示す。 生成物が活性部位から放出された後、酵素は元の状態に戻り、水分子が鉄核の遠位配位位置を占めるように戻る。
[[File:FeIVO 2.tif|thumb|left|シトクロムP450が、ヘムラジカルカチオンと結合した酸化鉄(IV)である「化合物I」の作用によって炭化水素をアルコールに変換する際に利用する[[Oxygen rebound mechanism/ja|酸素リバウンド機構]]。|300px]]

# モノ酸素化の代替経路は、"過酸化物シャント"（図中の経路 "S"）である。この経路は、過酸化物や次亜塩素酸塩のような酸素原子供与体による第二鉄-基質複合体の酸化を伴う。 仮想的な過酸化物 "XOOH "を図に示す。

===スペクトロスコピー===
基質の結合は酵素のスペクトル特性に反映され、390&nbsp;nmで吸光度が増加し、420&nbsp;nmで減少する。これは差スペクトルによって測定することができ、"type&nbsp;I"差スペクトルと呼ばれる（図の挿入グラフ参照）。 基質によっては、スペクトル特性に逆の変化、すなわち "逆タイプ&nbsp;I"スペクトルを引き起こすものもあり、その過程はまだ不明である。 ヘム鉄に直接結合する阻害剤とある種の基質は、430&nbsp;nmに極大、390&nbsp;nmに極小を持つタイプ&nbsp;II差スペクトルを生じる（図の挿入グラフ参照）。 還元当量がない場合、この複合体は安定なままである可能性があり、吸光度測定から結合の程度を''試験管内''で決定することができる。
C: 一酸化炭素（CO）が還元型P450に結合すると、触媒サイクルは中断される。この反応により、450&nbsp;nmに極大を持つ古典的なCO差スペクトルが得られる。しかし、COの触媒阻害作用はCYPによって異なり、CYP3Aファミリーは比較的影響を受けにくい。

==ヒトにおけるP450==
{{Anchor|P450s in humans}}
ヒトのP450は、主に[[mitochondria/ja|ミトコンドリア]]の内膜か細胞の[[endoplasmic reticulum/ja|小胞体]]に存在する膜関連タンパク質である。P450は何千もの[[endogenous/ja|内因性]]および[[exogenous/ja|外因性]]化学物質を代謝する。P450の中には、''CYP19''（[[aromatase/ja|アロマターゼ]]）のように1つの基質（またはごく少数の基質）のみを代謝するものもあれば、複数の[[Substrate (biochemistry)/ja|基質]]を代謝するものもある。これらの特徴の両方が、[[medicine/ja|医学]]における中心的な重要性の理由である。シトクロムP450酵素は身体のほとんどの組織に存在し、[[hormone/ja|ホルモン]]の合成と分解（[[estrogen/ja|エストロゲン]]と[[testosterone/ja|テストステロン]]の合成と代謝を含む）、[[cholesterol/ja|コレステロール]]の合成、[[vitamin D/ja|ビタミンD]]の代謝において重要な役割を担っている。シトクロムP450酵素はまた、主に[[liver/ja|肝臓]]において、[[drugs/ja|薬物]]や[[bilirubin/ja|ビリルビン]]のような内因性代謝産物など、潜在的に毒性のある化合物を代謝する働きもする。

[[Human Genome Project/ja|ヒトゲノムプロジェクト]]は、様々なシトクロームP450酵素をコードする57のヒト遺伝子を同定した。

===薬物代謝===
[[File:PropDrugsMetabCYP.png|thumb|400px|異なるP450ファミリーによって代謝される抗真菌薬の割合]]。

{{Further/ja|Drug metabolism/ja}}
P450は[[drug metabolism/ja|薬物代謝]]に関与する主要な酵素であり、代謝全体の約75％を占める。ほとんどの薬物は、P450によって直接または体外への[[excretion/ja|排泄]]促進によって不活性化される。しかし、多くの物質はP450によって[[bioactivation/ja|生物活性化]]され、[[antiplatelet drug/ja|抗血小板薬]]のような活性化合物を形成する。[[clopidogrel/ja|クロピドグレル]]やアヘン[[codeine/ja|コデイン]]のようにである。

CYP450酵素スーパーファミリーは57の活性サブセットからなり、7つがほとんどの医薬品の代謝に重要な役割を果たしている。第1相（解毒）におけるCYP450酵素（CYP1A2、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP3A4、CYP3A5）の量の変動は、遺伝子発現に個人差があるため、個人によって様々な影響を及ぼす可能性がある。このばらつきは、酵素の遺伝子多型によるもので、酵素の機能と発現にばらつきが生じる。個人の薬物代謝を最適化するためには、遺伝子検査を行い、個人のCYP450多型に対応した機能性食品や特定の植物栄養素を決定する必要がある。このような遺伝的変異を理解することは、薬物療法の有効性を高め、副作用を軽減するための個別化に役立つ。

===薬物相互作用===
多くの薬物は、アイソザイムの生合成を誘導する（[[Regulation of gene expression/ja|酵素誘導]]）か、P450の活性を直接阻害する（[[enzyme inhibition/ja|酵素阻害]]）かのどちらかによって、様々なP450[[isozyme/ja|アイソザイム]]の活性を増減させる可能性がある。古典的な例としては、[[CYP1A2/ja|CYP1A2]]、[[CYP2C9/ja|CYP2C9]]、[[CYP2C19/ja|CYP2C19]]、[[CYP3A4/ja|CYP3A4]]を誘導する[[phenytoin/ja|フェニトイン]]などの[[Anticonvulsant/ja|抗てんかん薬]]が挙げられる。

P450酵素活性の変化は、様々な薬物の[[drug interaction/ja|代謝]]や[[medical clearance/ja|クリアランス]]に影響を及ぼす可能性があるからである。例えば、ある薬物が別の薬物のP450を介した代謝を阻害した場合、2番目の薬物は体内で毒性レベルまで蓄積する可能性がある。したがって、このような薬物相互作用がある場合には、投与量を調節するか、P450系と相互作用しない薬物を選択する必要がある。このような薬物相互作用は、患者にとって極めて重要な薬物、重大な[[adverse effect/ja|副作用]]を伴う薬物、または[[therapeutic index/ja|治療指数]]の狭い薬物を使用する場合に特に考慮する必要があるが、どのような薬物でも薬物代謝の変化により血漿中濃度が変化する可能性がある。

CYP3A4の基質の多くは、[[amiodarone/ja|アミオダロン]]や[[carbamazepine/ja|カルバマゼピン]]などの[[therapeutic index/ja|治療指数]]が狭い薬物である。これらの薬物はCYP3A4によって代謝されるため、これらの薬物の[[mean plasma levels/ja|平均血漿中濃度]]は酵素阻害によって上昇することもあれば、酵素誘導によって低下することもある。

'''CYP450酵素の栄養調節： 誘導と阻害のバランス'''
アブラナ科の野菜はCYP1A1を誘導し、CYP1B1のアップレギュレーションを助ける。これらの野菜はベリー類とともに、体内でのエストロゲンの処理にも影響を与える。ベリー類はCYP1A1の活性を低下させると考えられているが、アブラナ科の野菜はCYP1B1酵素よりもCYP1A酵素の活性を高める可能性がある。

多くの食品に含まれる[[Resveratrol/ja|レスベラトロール]]、[[ellagic/ja|エラグ酸]]、[[quercetin/ja|ケルセチン]]は、CYP1A2活性に影響を及ぼす。

====他の物質との相互作用====
天然に存在する化合物もP450活性を誘導または阻害する可能性がある。例えば、[[bergamottin/ja|ベルガモッティン]]、[[dihydroxybergamottin/ja|ジヒドロキシベルガモッティン]]、[[paradicin-A/ja|パラダイシン-A]]など、[[grapefruit juice/ja|グレープフルーツジュース]]や他のいくつかの果汁に含まれる[[Bioactive compound/ja|生理活性化合物]]は、CYP3A4を介した[[Grapefruit–drug interactions/ja|特定の医薬品]]の代謝を阻害し、[[bioavailability/ja|バイオアベイラビリティ]]の上昇につながり、その結果、[[overdosing/ja|過剰投与]]の可能性が高いことがわかっている。このようなリスクがあるため、薬物を服用している間はグレープフルーツジュースや生のグレープフルーツを完全に避けることが通常勧められる。

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Other examples:
* [[Saint-John's wort]], a common [[herbal remedy]] [[Regulation of gene expression|induces]] [[CYP3A4]], but also inhibits [[CYP1A1]], [[CYP1B1]].
* [[Tobacco smoking]] induces [[CYP1A2]] (example CYP1A2 substrates are [[clozapine]], [[olanzapine]], and [[fluvoxamine]])
* At relatively high concentrations, [[carambola|starfruit]] juice has also been shown to inhibit [[CYP2A6]] and other P450s. [[Watercress]] is also a known inhibitor of the cytochrome P450 [[CYP2E1]], which may result in altered drug metabolism for individuals on certain medications (e.g., [[chlorzoxazone]]).
* [[Tributyltin]] has been found to inhibit the function of cytochrome P450, leading to masculinization of mollusks.
* [[Goldenseal]], with its two notable alkaloids [[berberine]] and [[hydrastine]], has been shown to alter P450-marker enzymatic activities (involving CYP2C9, CYP2D6, and CYP3A4).
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===Other specific P450 functions===
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====Steroid hormones====
[[File:Steroidogenesis.svg|thumb|400px|[[Steroidogenesis]], showing many of the enzyme activities that are performed by cytochrome P450 enzymes. HSD: Hydroxysteroid dehydrogenase.]]
A subset of cytochrome P450 enzymes play important roles in the synthesis of [[steroid hormone]]s ([[steroidogenesis]]) by the [[adrenal gland|adrenal]]s, [[gonad]]s, and peripheral tissue:
* [[CYP11A1]] (also known as P450scc or P450c11a1) in adrenal [[mitochondrion|mitochondria]] affects "the activity formerly known as 20,22-desmolase" (steroid 20α-hydroxylase, steroid 22-hydroxylase, cholesterol [[Side chain|side-chain]] scission).
* [[CYP11B1]] (encoding the protein P450c11β) found in the [[inner mitochondrial membrane]] of [[adrenal cortex]] has steroid 11β-hydroxylase, steroid [[18-hydroxylase]], and steroid 18-methyloxidase activities.
* [[CYP11B2]] (encoding the protein P450c11AS), found only in the mitochondria of the adrenal [[zona glomerulosa]], has steroid 11β-hydroxylase, steroid 18-hydroxylase, and steroid 18-methyloxidase activities.
* [[CYP17A1]], in endoplasmic reticulum of adrenal cortex has steroid 17α-hydroxylase and 17,20-lyase activities.
* [[CYP21A2]] (P450c21) in adrenal cortex conducts [[21-hydroxylase]] activity.
* [[CYP19A]] (P450arom, [[aromatase]]) in [[endoplasmic reticulum]] of [[gonads]], [[brain]], [[adipose tissue]], and elsewhere catalyzes [[aromatization]] of [[androgens]] to [[estrogens]].
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====Polyunsaturated fatty acids and eicosanoids====
Certain cytochrome P450 enzymes are critical in metabolizing [[polyunsaturated fatty acid]]s (PUFAs) to biologically active, intercellular [[cell signaling]] molecules ([[eicosanoid]]s) and/or metabolize biologically active metabolites of the PUFA to less active or inactive products.  These CYPs possess [[cytochrome P450 omega hydroxylase]] and/or [[epoxygenase]] enzyme activity.
* [[CYP1A1]], [[CYP1A2]], and [[CYP2E1]] metabolize endogenous PUFAs to signaling molecules: they metabolize [[arachidonic acid]] (i.e. AA) to 19-hydroxyeicosatetraenoic acid (i.e. 19-HETE; see [[20-Hydroxyeicosatetraenoic acid|20-hydroxyeicosatetraenoic acid]]); [[eicosapentaenoic acid]] (i.e. EPA) to [[epoxyeicosatetraenoic acid]]s (i.e. EEQs); and [[docosahexaenoic acid]] (i.e. DHA) to [[epoxydocosapentaenoic acid]]s (i.e. EDPs).
* [[CYP2C8]], [[CYP2C9]], [[CYP2C18]], [[CYP2C19]], and [[CYP2J2]] metabolize endogenous PUFAs to signaling molecules: they metabolize AA to [[epoxyeicosatetraenoic acid]]s (i.e. EETs); EPA to EEQs; and DHA to EDPs.
* [[CYP2S1]] metabolizes PUFA to signaling molecules: it metabolizes AA to EETs and EPA to EEQs.
* [[CYP3A4]] metabolizes AA to EET signaling molecules.
* [[CYP4A11]] metabolizes endogenous PUFAs to signaling molecules: it metabolizes AA to 20-HETE and EETs; it also hydroxylates DHA to 22-hydroxy-DHA (i.e. 12-HDHA).
* [[CYP4F2]], CYP4F3A, and CYP4F3B (see [[CYP4F3]] for latter two CYPs) metabolize PUFAs to signaling molecules: they metabolizes AA to 20-HETE. They also metabolize EPA to 19-hydroxyeicosapentaenoic acid (19-HEPE) and 20-hydroxyeicosapentaenoic acid (20-HEPE) as well as metabolize DHA to 22-HDA.  They also inactivate or reduce the activity of signaling molecules: they metabolize [[leukotriene B4]] (LTB4) to 20-hydroxy-LTB4, [[5-hydroxyeicosatetraenoic acid]] (5-HETE) to 5,20-diHETE, [[5-oxo-eicosatetraenoic acid]] (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, [[12-hydroxyeicosatetraenoic acid]] (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and [[lipoxin]]s to 20-hydroxy products.
* [[CYP4F8]] and [[CYP4F12]] metabolize PUFAs to signaling molecules: they metabolizes EPA to EEQs and DHA to EDPs. They also metabolize AA to 18-hydroxyeicosatetraenoic acid (18-HETE) and 19-HETE.
* [[CYP4F11]] inactivates or reduces the activity of signaling molecules: it metabolizes LTB4 to 20-hydroxy-LTB4, (5-HETE) to 5,20-diHETE, (5-oxo-ETE) to 5-oxo,20-hydroxy-ETE, (12-HETE) to 12,20-diHETE, EETs to 20-hydroxy-EETs, and [[lipoxin]]s to 20-hydroxy products.
* [[CYP4F22]] ω-hydroxylates extremely long "[[very long chain fatty acids]]", i.e. fatty acids that are 28 or more carbons long. The ω-hydroxylation of these special fatty acids is critical to creating and maintaining the skin's water barrier function; autosomal recessive inactivating mutations of CYP4F22 are associated with the [[Lamellar ichthyosis]] subtype of [[Congenital ichthyosiform erythrodema]] in humans.
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===CYP families in humans===
Humans have 57 genes and more than 59 [[pseudogene]]s divided among 18 families of cytochrome P450 genes and 43 subfamilies. This is a summary of the genes and of the proteins they encode. See the homepage of the cytochrome P450 Nomenclature Committee for detailed information.
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{| class="wikitable"
| '''Family''' || '''Function''' || '''Members''' || '''Genes''' || '''Pseudogenes'''
 |-
 | '''CYP1''' ||  drug and steroid (especially [[estrogen]]) metabolism, [[benzo(a)pyrene|benzo[''a'']pyrene]] toxification (forming [[(+)-Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide|(+)-benzo[''a'']pyrene-7,8-dihydrodiol-9,10-epoxide]])   || 3 subfamilies, 3 genes, 1 [[pseudogene]]  ||  [[CYP1A1]], [[CYP1A2]], [[CYP1B1]] || [[CYP1D1P]]
 |-
 | '''CYP2''' ||  drug and [[steroid]] metabolism   || 13 subfamilies, 16 genes, 16 [[pseudogene]]s  ||  [[CYP2A6]], [[CYP2A7]], [[CYP2A13]], [[CYP2B6]], [[CYP2C8]], [[CYP2C9]], [[CYP2C18]], [[CYP2C19]], [[CYP2D6]], [[CYP2E1]], [[CYP2F1]], [[CYP2J2]], [[CYP2R1]], [[CYP2S1]], [[CYP2U1]], [[CYP2W1]] || Too many to list
 |-
 | '''CYP3''' ||  drug and [[steroid]] (including [[testosterone]]) metabolism   || 1 subfamily, 4 genes, 4 [[pseudogene]]s  ||  [[CYP3A4]], [[CYP3A5]], [[CYP3A7]], [[CYP3A43]] || CYP3A51P, CYP3A52P, CYP3A54P, CYP3A137P
 |-
 | '''CYP4''' ||  [[arachidonic acid]] or fatty acid metabolism   || 6 subfamilies, 12 genes, 10  [[pseudogene]]s  ||  [[CYP4A11]], [[CYP4A22]], [[CYP4B1]], [[CYP4F2]], [[CYP4F3]], [[CYP4F8]], [[CYP4F11]], [[CYP4F12]], [[CYP4F22]], [[CYP4V2]], [[CYP4X1]], [[CYP4Z1]] || Too many to list
 |-
 | '''CYP5''' ||  [[thromboxane]] A<sub>2</sub> [[thromboxane-A synthase|synthase]]   || 1 subfamily, 1 gene  ||  [[Thromboxane-A synthase|CYP5A1]] ||
 |-
 | '''CYP7''' ||  [[bile acid]] biosynthesis 7-alpha hydroxylase of steroid nucleus   || 2 subfamilies, 2 genes  ||  [[CYP7A1]], [[CYP7B1]] ||
 |-
 | '''CYP8'''  || ''varied''  || 2 subfamilies, 2 genes  ||  [[CYP8A1]] ([[prostacyclin]] synthase), [[CYP8B1]] (bile acid biosynthesis) ||
 |-
 | '''CYP11''' ||  [[steroid]] biosynthesis   || 2 subfamilies, 3 genes  ||  [[CYP11A1]], [[CYP11B1]], [[CYP11B2]] ||
 |-
 | '''CYP17''' ||  [[steroid]] biosynthesis, 17-alpha hydroxylase  || 1 subfamily, 1 gene   ||  [[CYP17A1]] ||
 |-
 | '''CYP19''' ||  [[steroid]] biosynthesis: [[aromatase]] synthesizes [[estrogen]]    || 1 subfamily, 1 gene  ||  [[CYP19A1]] ||
 |-
 | '''CYP20''' ||  unknown function   || 1 subfamily, 1 gene  ||  [[CYP20A1]] ||
 |-
 | '''CYP21''' ||  [[steroid]] biosynthesis   || 1 subfamilies, 1 gene, 1 pseudogene  ||  [[CYP21A2]] || [[CYP21A1P]]
 |-
 | '''CYP24''' ||  [[vitamin D]] degradation   || 1 subfamily, 1 gene  ||  [[CYP24A1]] ||
 |-
 | '''[[CYP26]]''' ||  [[retinoic acid]] hydroxylase   || 3 subfamilies, 3 genes  ||  [[CYP26A1]], [[CYP26B1]], [[CYP26C1]] ||
 |-
 | '''CYP27''' || ''varied''  || 3 subfamilies, 3 genes  ||  [[CYP27A1]] ([[bile acid]] biosynthesis), [[CYP27B1]] (vitamin D<sub>3</sub> 1-alpha hydroxylase, activates vitamin D<sub>3</sub>), [[CYP27C1]] (vitamin A1 to A2) ||
 |-
 | '''CYP39''' ||  7-alpha hydroxylation of 24-hydroxycholesterol   || 1 subfamily, 1 gene ||  [[CYP39A1]] ||
 |-
 | '''CYP46''' ||  [[cholesterol]] 24-hydroxylase   || 1 subfamily, 1 gene, 1 pseudogene  ||  [[CYP46A1]] || CYP46A4P
 |-
 | '''CYP51''' ||  [[cholesterol]] biosynthesis   || 1 subfamily, 1 gene, 3 pseudogenes  ||  [[CYP51A1]] ([[lanosterol]] 14-alpha demethylase) || CYP51P1, CYP51P2, CYP51P3
|}
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== P450s in other species ==
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=== Animals ===
Other animals often have more P450 genes than humans do. Reported numbers range from 35 genes in the sponge ''[[Amphimedon queenslandica]]'' to 235 genes in the cephalochordate ''[[Branchiostoma floridae]]''. [[Mice]] have genes for 101 P450s, and [[sea urchin]]s have even more (perhaps as many as 120 genes).
Most CYP enzymes are presumed to have monooxygenase activity, as is the case for most mammalian CYPs that have been investigated (except for, e.g., [[aromatase|CYP19]] and [[Thromboxane-A synthase|CYP5]]). [[Gene]] and [[genome sequencing]] is far outpacing [[biochemical]] characterization of enzymatic function, though many genes with close [[homology (biology)|homology]] to CYPs with known function have been found, giving clues to their functionality.
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The classes of P450s most often investigated in non-human animals are those either involved in [[developmental biology|development]] (e.g., [[retinoic acid]] or [[hormone]] metabolism) or involved in the metabolism of toxic compounds (such as [[heterocyclic amine]]s or [[polyaromatic hydrocarbons]]). Often there are differences in [[gene regulation]] or [[enzyme function]] of P450s in related animals that explain observed differences in susceptibility to toxic compounds (ex. canines' inability to metabolize xanthines such as caffeine). Some drugs undergo metabolism in both species via different enzymes, resulting in different metabolites, while other drugs are metabolized in one species but excreted unchanged in another species. For this reason, one species's reaction to a substance is not a reliable indication of the substance's effects in humans. A species of Sonoran Desert Drosophila that uses an upregulated expression of the [[CYP28A1]] gene for detoxification of cacti rot is ''[[Drosophila mettleri]]''. Flies of this species have adapted an upregulation of this gene due to exposure of high levels of alkaloids in host plants.
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P450s have been extensively examined in [[mice]], [[rat]]s, [[dog]]s, and less so in [[zebrafish]], in order to facilitate use of these [[model organisms]] in [[drug discovery]] and [[toxicology]]. Recently P450s have also been discovered in avian species, in particular turkeys, that may turn out to be a useful model for cancer research in humans. [[CYP1A5]] and [[CYP3A37]] in turkeys were found to be very similar to the human [[CYP1A2]] and [[CYP3A4]] respectively, in terms of their kinetic properties as well as in the metabolism of aflatoxin B1.
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CYPs have also been heavily studied in [[insect]]s, often to understand [[pesticide resistance]].  For example, [[CYP6G1]] is linked to insecticide resistance in [[DDT]]-resistant ''[[Drosophila melanogaster]]'' and [[CYP6M2]] in the mosquito [[malaria]] vector ''[[Anopheles gambiae]]'' is capable of directly metabolizing [[pyrethroids]].
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=== Microbial ===
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Microbial cytochromes P450 are often soluble enzymes and are involved in diverse metabolic processes. In bacteria the distribution of P450s is very variable with many bacteria having no identified P450s (e.g. ''E.coli''). Some bacteria, predominantly actinomycetes, have numerous P450s. Those so far identified are generally involved in either biotransformation of xenobiotic compounds (e.g. [[Vitamin D3 dihydroxylase|CYP105A1]] from ''[[Streptomyces griseolus]]'' metabolizes [[sulfonylurea herbicide]]s to less toxic derivatives) or are part of specialised metabolite biosynthetic pathways (e.g. [[CYP170B1]] catalyses production of the [[sesquiterpenoid]] albaflavenone in ''[[Streptomyces albus]]''). Although no P450 has yet been shown to be essential in a microbe, the [[CYP105 family]] is highly conserved with a representative in every [[streptomycete]] genome sequenced so far. Due to the solubility of bacterial P450 enzymes, they are generally regarded as easier to work with than the predominantly membrane bound eukaryotic P450s. This, combined with the remarkable chemistry they catalyse, has led to many studies using the [[heterologously expressed protein]]s in vitro. Few studies have investigated what P450s do in vivo, what the natural substrate(s) are and how P450s contribute to survival of the bacteria in the natural environment.Three examples that have contributed significantly to structural and mechanistic studies are listed here, but many different families exist.
* [[Cytochrome P450 cam]] (CYP101A1) originally from ''[[Pseudomonas putida]]'' has been used as a model for many cytochromes P450 and was the first cytochrome P450 three-dimensional protein structure solved by X-ray crystallography.  This enzyme is part of a camphor-hydroxylating catalytic cycle consisting of two electron transfer steps from [[putidaredoxin]], a 2Fe-2S cluster-containing protein cofactor.
* [[Cytochrome P450 eryF]] (CYP107A1) originally from the actinomycete bacterium ''[[Saccharopolyspora erythraea]]'' is responsible for the biosynthesis of the [[antibiotic]] [[erythromycin]] by C6-hydroxylation of the macrolide 6-deoxyerythronolide B.
* [[Cytochrome P450 BM3]] (CYP102A1) from the soil bacterium ''[[Bacillus megaterium]]'' catalyzes the NADPH-dependent hydroxylation of several [[long-chain fatty acid]]s at the ω–1 through ω–3 positions. Unlike almost every other known CYP (except CYP505A1, cytochrome P450 foxy), it constitutes a natural fusion protein between the CYP domain and an electron donating cofactor. Thus, BM3 is potentially very useful in biotechnological applications.
* Cytochrome P450 119 ([[CYP119A1]]) isolated from the [[thermophillic]] archea ''[[Sulfolobus solfataricus]]''  has been used in a variety of mechanistic studies. Because thermophillic enzymes evolved to function at high temperatures, they tend to function more slowly at room temperature (if at all) and are therefore excellent mechanistic models.
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=== Fungi ===
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The commonly used [[Antifungal drug#Imidazole, triazole, and thiazole antifungals|azole]] class antifungal drugs work by inhibition of the fungal [[cytochrome P450 14α-demethylase]]. This interrupts the conversion of [[lanosterol]] to [[ergosterol]], a component of the fungal cell membrane.  (This is useful only because humans' P450 have a different sensitivity; this is how this class of [[antifungals]] work.)
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Significant research is ongoing into fungal P450s, as a number of fungi are [[Pathogenic fungi|pathogenic]] to humans (such as [[Candida (fungus)|Candida]] [[yeast]] and [[Aspergillus]]) and to plants.
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''[[Cunninghamella elegans]]'' is a candidate for use as a model for mammalian drug metabolism.
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=== Plants ===
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Cytochromes P450 are involved in a variety of processes of plant growth, development, and defense. It is estimated that P450 genes make up approximately 1% of the plant genome. These enzymes lead to various [[fatty acid]] conjugates, [[plant hormone]]s, [[secondary metabolite]]s, [[lignin]]s, and a variety of defensive compounds.
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Cytochromes P450 play an important role in plant defense– involvement in phytoalexin biosynthesis, hormone metabolism, and biosynthesis of diverse secondary metabolites. The expression of cytochrome p450 genes is regulated in response to environmental stresses indicative of a critical role in plant defense mechanisms.
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Phytoalexins have shown to be important in plant defense mechanisms as they are antimicrobial compounds produced by plants in response to plant pathogens. Phytoalexins are not pathogen-specific, but rather plant-specific; each plant has its own unique set of phytoalexins. However, they can still attack a wide range of different pathogens. Arabidopsis is a plant closely related to cabbage and mustard and produces the phytoalexin camalexin. Camalexin originates from tryptophan and its biosynthesis involves five cytochrome P450 enzymes. The five cytochrome P450 enzymes include CYP79B2, CYP79B3, CYP71A12, CYP71A13, and CYP71B15. The first step of camalexin biosynthesis produces indole-3-acetaldoxime (IAOx) from tryptophan and is catalyzed by either CYP79B2 or CYP79B3. IAOx is then immediately converted to indole-3-acetonitrile (IAN) and is controlled by either CYP71A13 or its homolog CYP71A12. The last two steps of the biosynthesis pathway of camalexin are catalyzed by CYP71B15. In these steps, indole-3-carboxylic acid (DHCA) is formed from cysteine-indole-3-acetonitrile (Cys(IAN)) followed by the biosynthesis of camalexin. There are some intermediate steps within the pathway that remain unclear, but it is well understood that cytochrome P450 is pivotal in camalexin biosynthesis and that this phytoalexin plays a major role in plant defense mechanisms.
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Cytochromes P450 are largely responsible for the synthesis of the jasmonic acid (JA), a common hormonal defenses against abiotic and biotic stresses for plant cells. For example, a P450, CYP74A is involved in the dehydration reaction to produce an insatiable allene oxide from hydroperoxide. JA chemical reactions are critical in the presence of biotic stresses that can be caused by plant wounding, specifically shown in the plant, Arabidopsis. As a prohormone, jasmonic acid must be converted to the JA-isoleucine (JA-Ile) conjugate by JAR1 catalysation in order to be considered activated. Then, JA-Ile synthesis leads to the assembly of the co-receptor complex compo`sed of COI1 and several JAZ proteins. Under low JA-Ile conditions, the JAZ protein components act as transcriptional repressors to suppress downstream JA genes. However, under adequate JA-Ile conditions, the JAZ proteins are ubiquitinated and undergo degradation through the 26S proteasome, resulting in functional downstream effects. Furthermore, several CYP94s (CYP94C1 and CYP94B3) are related to JA-Ile turnover and show that JA-Ile oxidation status impacts plant signaling in a catabolic manner. Cytochrome P450 hormonal regulation in response to extracellular and intracellular stresses is critical for proper plant defense response. This has been proven through thorough analysis of various CYP P450s in jasmonic acid and phytoalexin pathways.
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[[Cytochrome P450 aromatic O-demethylase]], which is made of two distinct promiscuous parts: a cytochrome P450 protein (GcoA) and three domain reductase, is significant for its ability to convert Lignin, the aromatic biopolymer common in plant cell walls, into renewable carbon chains in a catabolic set of reactions. In short, it is a facilitator of a critical step in Lignin conversion.
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==InterPro subfamilies==
[[InterPro]] subfamilies:
* Cytochrome P450, B-class {{InterPro|IPR002397}}
* Cytochrome P450, mitochondrial {{InterPro|IPR002399}}
* Cytochrome P450, E-class, group I {{InterPro|IPR002401}}
* Cytochrome P450, E-class, group II {{InterPro|IPR002402}}
* Cytochrome P450, E-class, group IV {{InterPro|IPR002403}}
* [[Aromatase]]
Clozapine, imipramine, paracetamol, phenacetin Heterocyclic aryl amines
Inducible and CYP1A2 5-10% deficient
oxidize uroporphyrinogen to uroporphyrin (CYP1A2) in heme metabolism, but they may have additional undiscovered endogenous substrates.
are inducible by some polycyclic hydrocarbons, some of which are found in cigarette smoke and charred food.
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These enzymes are of interest, because in assays, they can activate compounds to carcinogens.
High levels of CYP1A2 have been linked to an increased risk of colon cancer. Since the 1A2 enzyme can be induced by cigarette smoking, this links smoking with colon cancer.
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==歴史==
{{Anchor|History}}
1963年、[[:en:Ronald W. Estabrook|エスタブルック]]、[[:en:David Y. Cooper|クーパー]]、[[:en:Otto Rosenthal|ローゼンタール]]は、ステロイドホルモン合成と薬物代謝における触媒としてのCYPの役割を説明した。植物では、これらのタンパク質は[[secondary metabolite/ja|防御化合物]]、脂肪酸、ホルモンの生合成に重要である。

== こちらも参照 ==
{{Portal|Biology}}
* [[Steroidogenic enzyme/ja]]
* [[Cytochrome P450 oxidoreductase deficiency/ja]]
* [[CYP11 family/ja]]
* [[Cytochrome P450 engineering/ja]]

== さらに読む ==
{{Refbegin|32em}}
* {{cite journal | vauthors = Gelboin HV, Krausz K | title = Monoclonal antibodies and multifunctional cytochrome P450: drug metabolism as paradigm | journal = Journal of Clinical Pharmacology | volume = 46 | issue = 3 | pages = 353–372 | date = March 2006 | pmid = 16490812 | doi = 10.1177/0091270005285200 | s2cid = 33325397 }}
* {{cite journal | vauthors = Gelboin HV, Krausz KW, Gonzalez FJ, Yang TJ | title = Inhibitory monoclonal antibodies to human cytochrome P450 enzymes: a new avenue for drug discovery | journal = Trends in Pharmacological Sciences | volume = 20 | issue = 11 | pages = 432–438 | date = November 1999 | pmid = 10542439 | doi = 10.1016/S0165-6147(99)01382-6 }}
* {{Cite web|url=https://home.ccr.cancer.gov/metabolism/mab1.htm|title=Cytochrome P450 Mediated Drug and Carcinogen Metabolism using Monoclonal Antibodies|website=home.ccr.cancer.gov|access-date=2018-04-02}}
* {{cite journal | vauthors = Krausz KW, Goldfarb I, Buters JT, Yang TJ, Gonzalez FJ, Gelboin HV | title = Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9, and 2C19 | journal = Drug Metabolism and Disposition | volume = 29 | issue = 11 | pages = 1410–1423 | date = November 2001 | pmid = 11602516 | url = http://dmd.aspetjournals.org/content/29/11/1410 }}
* {{cite journal | vauthors = Gonzalez FJ, Gelboin HV | title = Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins | journal = Drug Metabolism Reviews | volume = 26 | issue = 1–2 | pages = 165–183 | date = 1994 | pmid = 8082563 | doi = 10.3109/03602539409029789 }}
* {{cite journal | vauthors = Estabrook RW | title = A passion for P450s (Remembrances of the early history of research on cytochrome P450) | journal = Drug Metabolism and Disposition | volume = 31 | issue = 12 | pages = 1461–1473 | date = December 2003 | pmid = 14625342 | doi = 10.1124/dmd.31.12.1461 | s2cid = 43655270 }}
{{Refend}}

== 外部リンク ==
{{Commons category}}
* {{cite web | vauthors = Degtyarenko K | url = http://www.icgeb.org/~p450srv/ | title = Directory of P450-containing Systems | date = 2009-01-09 | publisher = [[Wikipedia:International Centre for Genetic Engineering and Biotechnology|International Centre for Genetic Engineering and Biotechnology]] | access-date = 2009-02-10 | archive-url = https://web.archive.org/web/20160716081404/http://www.icgeb.org/~p450srv/ | archive-date = 2016-07-16 | url-status = dead }}
* {{cite web | vauthors = Flockhart DA | url = https://www.pharmvar.org/ | title = Human Cytochrome P450 (CYP) Allele Nomenclature Committee | date = 2008-09-04 | publisher = [[Wikipedia:Karolinska Institutet|Karolinska Institutet]] | access-date = 2009-02-10}}
* {{cite web | vauthors = Preissner S | url = http://bioinformatics.charite.de/supercyp/ | title = Cytochrome P450 database | year = 2010 | publisher = Nucleic Acids Research | access-date = 2011-08-02 | archive-date = 2011-11-03 | archive-url = https://web.archive.org/web/20111103123642/http://bioinformatics.charite.de/supercyp/ | url-status = dead }}
* {{cite web | vauthors = Sigaroudi A, Vollbrecht H | url = http://www.kisch.ch/ | title = pharmacokinetic interaction table | year = 2019 | publisher = Sigaroudi & Vollbrecht }}
* {{cite web | vauthors = Sim SC | url = http://medicine.iupui.edu/flockhart/ | title = Cytochrome P450 drug interaction table | year = 2007 | publisher =  [[Wikipedia:Indiana University-Purdue University Indianapolis|Indiana University-Purdue University Indianapolis]] | access-date = 2009-02-10}}

{{Hemeproteins/ja}}
{{Cytochrome P450/ja}}
{{Enzymes/ja}}

[[Category:Cytochrome P450| ]]
[[Category:EC 1.14]]
[[Category:Pharmacokinetics]]
[[Category:Metabolism]]
[[Category:Integral membrane proteins]]