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{{short description|Biochemical modification of drugs or foreign compounds by living organisms}}
{{About|the scientific concept of drug metabolism|alternative medicine|Detoxification (alternative medicine)}}

'''Drug metabolism''' is the [[metabolism|metabolic breakdown]] of [[drug]]s by living [[organism]]s, usually through specialized [[enzyme|enzymatic]] systems. More generally, '''xenobiotic metabolism''' (from the Greek [[xenos (Greek)|xenos]] "stranger" and biotic "related to living beings") is the set of [[metabolic pathway]]s that modify the chemical structure of [[xenobiotic]]s, which are compounds foreign to an organism's normal biochemistry, such as any [[drug]] or [[poison]]. These pathways are a form of [[biotransformation]] present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to [[detoxification|detoxify]] poisonous compounds (although in some cases the [[reaction intermediate|intermediate]]s in xenobiotic metabolism can themselves cause toxic effects). The study of drug metabolism is called [[pharmacokinetics]].

The metabolism of [[pharmaceutical drug]]s is an important aspect of [[pharmacology]] and [[medicine]]. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects [[multidrug resistance]] in [[infectious disease]]s and in [[chemotherapy]] for [[cancer]], and the actions of some drugs as [[substrate (chemistry)|substrates]] or [[enzyme inhibitor|inhibitors]] of enzymes involved in xenobiotic metabolism are a common reason for hazardous [[drug interaction]]s. These pathways are also important in [[environmental science]], with the xenobiotic metabolism of [[microorganism]]s determining whether a pollutant will be broken down during [[bioremediation]], or [[persistent organic pollutant|persist]] in the environment. The enzymes of xenobiotic metabolism, particularly the [[glutathione S-transferase]]s are also important in agriculture, since they may produce resistance to [[pesticide]]s and [[herbicide]]s.

Drug metabolism is divided into three phases. In phase I, enzymes such as [[cytochrome P450 oxidase]]s introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalysed by [[transferase]] enzymes such as [[glutathione S-transferase]]s. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognised by [[Efflux (microbiology)|efflux transporters]] and pumped out of cells. Drug metabolism often converts [[lipophilic]] compounds into [[hydrophile|hydrophilic]] products that are more readily [[excretion|excreted]].{{cn|date=March 2022}}

== Permeability barriers and detoxification ==

The exact compounds an organism is exposed to will be largely unpredictable, and may differ widely over time; these are major characteristics of xenobiotic toxic stress.<ref name=Jakoby/> The major challenge faced by xenobiotic detoxification systems is that they must be able to remove the almost-limitless number of xenobiotic compounds from the complex mixture of chemicals involved in normal [[metabolism]]. The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity [[enzyme|enzymatic]] systems.

All organisms use [[cell membrane]]s as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these [[cell membrane]]s, and the uptake of useful molecules is mediated through [[transport protein]]s that specifically select substrates from the extracellular mixture. This selective uptake means that most [[hydrophile|hydrophilic]] molecules cannot enter cells, since they are not recognised by any specific transporters.<ref name="pmid12869659">{{cite journal |vauthors=Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y | title = Impact of drug transporter studies on drug discovery and development | journal = Pharmacol. Rev. | volume = 55 | issue = 3 | pages = 425–61 |date=September 2003 | pmid = 12869659 | doi = 10.1124/pr.55.3.1 | s2cid = 724685 }}</ref> In contrast, the diffusion of [[hydrophobe|hydrophobic]] compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude [[lipid]]-soluble xenobiotics using membrane barriers.

However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound.<ref name=Jakoby/> Useful metabolites are excluded since they are polar, and in general contain one or more charged groups.

The detoxification of the reactive by-products of normal metabolism cannot be achieved by the systems outlined above, because these species are derived from normal cellular constituents and usually share their polar characteristics. However, since these compounds are few in number, specific enzymes can recognize and remove them. Examples of these specific detoxification systems are the [[glyoxalase system]], which removes the reactive [[aldehyde]] methylglyoxal,<ref name="pmid2198020">{{cite journal | author = Thornalley PJ | title = The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life | journal = Biochem. J. | volume = 269 | issue = 1 | pages = 1–11 |date=July 1990 | pmid = 2198020 | pmc = 1131522 | doi = 10.1042/bj2690001}}</ref> and the various antioxidant systems that eliminate [[reactive oxygen species]].<ref name="Sies">{{cite journal | author = Sies H | title = Oxidative stress: oxidants and antioxidants | journal = Exp. Physiol. | volume = 82 | issue = 2 | pages = 291–5 | date = March 1997 | pmid = 9129943 | doi = 10.1113/expphysiol.1997.sp004024 | doi-access = free }}</ref>

== {{anchor|Phases}} Phases of detoxification ==

[[File:Xenobiotic metabolism.png|thumb|350px|right|Phases I and II of the metabolism of a lipophilic xenobiotic.]]
The metabolism of xenobiotics is often divided into three phases: modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells.

=== Phase I – modification ===

In phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the [[cytochrome P450|cytochrome P-450-dependent mixed-function oxidase system]]. These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates.<ref name="pmid11409933">{{cite journal | author = Guengerich FP | title = Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity | journal = Chem. Res. Toxicol. | volume = 14 | issue = 6 | pages = 611–50 |date=June 2001 | pmid = 11409933 | doi = 10.1021/tx0002583 }}</ref> The reaction mechanism of the P-450 oxidases proceeds through the reduction of cytochrome-bound oxygen and the generation of a highly-reactive oxyferryl species, according to the following scheme:<ref name="pmid10698731">{{cite journal |vauthors=Schlichting I, Berendzen J, Chu K, Stock AM, Maves SA, Benson DE, Sweet RM, Ringe D, Petsko GA, Sligar SG | title = The catalytic pathway of cytochrome p450cam at atomic resolution | journal = Science | volume = 287 | issue = 5458 | pages = 1615–22 |date=March 2000 | pmid = 10698731 | doi = 10.1126/science.287.5458.1615 | bibcode = 2000Sci...287.1615S }}</ref>

:O2 + NADPH + H+ + RH → NADP+ + H2O + ROH

Phase I reactions (also termed nonsynthetic reactions) may occur by [[oxidation]], [[Redox|reduction]], [[hydrolysis]], [[cyclization]], [[decyclization]], and addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a [[Cytochrome P450 oxidase|cytochrome P450]] monooxygenase (often abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism include [[phenothiazine]]s, [[Paracetamol#Metabolism|paracetamol]], and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an [[endogenous]] [[substrate (chemistry)|substrate]] combines with the newly incorporated functional group to form a highly [[polar conjugate]].

A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (a [[prodrug]]) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one ([[toxification]]). Simple hydrolysis in the stomach is normally an innocuous reaction, however there are exceptions. For example, phase I metabolism converts [[acetonitrile]] to HOCH2CN, which rapidly dissociates into [[formaldehyde]] and [[hydrogen cyanide]].<ref>{{Cite web|url=http://www.inchem.org/documents/ehc/ehc/ehc154.htm|title=Acetonitrile (EHC 154, 1993)|website=www.inchem.org|access-date=2017-05-03|archive-date=2017-05-22|archive-url=https://web.archive.org/web/20170522135955/http://www.inchem.org/documents/ehc/ehc/ehc154.htm|url-status=live}}</ref>

Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts.<ref name="pmid19039354">{{cite journal |vauthors=Akagah B, Lormier AT, Fournet A, Figadère B | title = Oxidation of antiparasitic 2-substituted quinolines using metalloporphyrin catalysts: scale-up of a biomimetic reaction for metabolite production of drug candidates | journal = Org. Biomol. Chem. | volume = 6 | issue = 24 | pages = 4494–7 |date=December 2008 | pmid = 19039354 | doi = 10.1039/b815963g }}</ref> This example of a [[biomimetic]] reaction tends to give products that often contains the Phase I metabolites. As an example, the major metabolite of the pharmaceutical [[trimebutine]], desmethyltrimebutine (nor-trimebutine), can be efficiently produced by in vitro oxidation of the commercially available drug. Hydroxylation of an N-methyl group leads to expulsion of a molecule of [[formaldehyde]], while oxidation of the O-methyl groups takes place to a lesser extent.

==== Oxidation ====
* [[Cytochrome P450 oxidase|Cytochrome P450 monooxygenase system]]
* [[Flavin-containing monooxygenase system]]
* [[Alcohol dehydrogenase]] and [[aldehyde dehydrogenase]]
* [[Monoamine oxidase]]
* Co-oxidation by [[peroxidase]]s

==== Reduction ====
* [[Cytochrome P450 reductase|NADPH-cytochrome P450 reductase]]
Cytochrome P450 reductase, also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR, is a membrane-bound enzyme required for electron transfer to cytochrome P450 in the microsome of the eukaryotic cell from a FAD- and FMN-containing enzyme NADPH:cytochrome P450 reductase
The general scheme of electron flow in the POR/P450 system is:
NADPH
→
FAD
→
FMN
→
P450
→
O2
* [[Cytochrome P450 reductase|Reduced (ferrous) cytochrome P450]]

During reduction reactions, a chemical can enter ''futile cycling'', in which it gains a free-radical electron, then promptly loses it to [[oxygen]] (to form a [[superoxide anion]]).

==== Hydrolysis ====
* [[Esterase]]s and [[amidase]]
* [[Epoxide hydrolase]]

=== Phase II – conjugation {{anchor|Conjugation}} ===

In subsequent phase II reactions, these activated xenobiotic metabolites are [[Biotransformation#Phase І reaction|conjugated]] with charged species such as [[glutathione]] (GSH), [[sulfate]], [[glycine]], or [[glucuronic acid]]. Sites on drugs where conjugation reactions occur include [[carboxy]] (-COOH), [[Hydroxyl|hydroxy]] (-OH), [[amino]] (NH2), and [[thiol]] (-SH) groups. Products of conjugation reactions have increased molecular weight and tend to be less active than their substrates, unlike Phase I reactions which often produce [[active metabolites]]. The addition of large anionic groups (such as GSH) detoxifies reactive [[electrophile]]s and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported.

These reactions are catalysed by a large group of broad-specificity transferases, which in combination can metabolise almost any hydrophobic compound that contains nucleophilic or electrophilic groups.<ref name=Jakoby>{{cite journal | vauthors = Jakoby WB, Ziegler DM | title = The enzymes of detoxication | journal = J. Biol. Chem. | volume = 265 | issue = 34 | pages = 20715–8 | date = December 1990 | doi = 10.1016/S0021-9258(17)45272-0 | pmid = 2249981 | url = http://www.jbc.org/cgi/reprint/265/34/20715 | doi-access = free | access-date = 2012-12-29 | archive-date = 2009-06-21 | archive-url = https://web.archive.org/web/20090621070323/http://www.jbc.org/cgi/reprint/265/34/20715 | url-status = live }}</ref> One of the most important classes of this group is that of the [[glutathione S-transferase]]s (GSTs).

{|class="wikitable"
! Mechanism !! Involved enzyme !! Co-factor !! Location !! Sources
|-
| [[methylation]] || [[methyltransferase]] || [[S-adenosyl-L-methionine]] || liver, kidney, lung, CNS || <ref name="Liston_2001">{{cite journal |vauthors=Liston HL, Markowitz JS, DeVane CL | title = Drug glucuronidation in clinical psychopharmacology | journal = J Clin Psychopharmacol | volume = 21 | issue = 5 | pages = 500–15 |date=October 2001 | pmid = 11593076 | doi = 10.1097/00004714-200110000-00008| s2cid = 6068811 }}</ref>
|-
| [[sulphation]] || [[sulfotransferase]]s || [[3'-phosphoadenosine-5'-phosphosulfate]] || liver, kidney, intestine || <ref name="Liston_2001"/>
|-
| [[acetylation]] ||
* [[N-acetyltransferase]]s
* [[bile acid-CoA:amino acid N-acyltransferase]]s
| [[acetyl coenzyme A]] || liver, lung, spleen, gastric mucosa, [[red blood cell|RBCs]], lymphocytes
| <ref name="Liston_2001"/>
|-
| [[glucuronidation]] || [[UDP-glucuronosyltransferase]]s || [[UDP-glucuronic acid]] || liver, kidney, intestine, lung, skin, prostate, brain || <ref name="Liston_2001"/>
|-
| glutathione conjugation || [[glutathione S-transferase]]s || [[glutathione]] || liver, kidney || <ref name="Liston_2001"/>
|-
| glycine conjugation || Two step process:
# [[XM-ligase]] (forms a xenobiotic acyl-CoA)
# [[Glycine N-acyltransferase]] (forms the glycine conjugate)
| [[glycine]] || liver, kidney || <ref name="Glycine conjugation review">{{cite journal | vauthors = Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA | title = Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 9 | issue = 9 | pages = 1139–1153 | date = September 2013 | pmid = 23650932 | doi = 10.1517/17425255.2013.796929 | s2cid = 23738007 | quote = Glycine conjugation of mitochondrial acyl-CoAs, catalyzed by glycine N-acyltransferase (GLYAT, E.C. 2.3.1.13), is an important metabolic pathway responsible for maintaining adequate levels of free coenzyme A (CoASH). However, because of the small number of pharmaceutical drugs that are conjugated to glycine, the pathway has not yet been characterized in detail. Here, we review the causes and possible consequences of interindividual variation in the glycine conjugation pathway. ... Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.}}</ref>
|}

=== Phase III – further modification and excretion ===

After phase II reactions, the xenobiotic conjugates may be further metabolized. A common example is the processing of glutathione conjugates to [[acetylcysteine]] (mercapturic acid) conjugates.<ref name="pmid4892500">{{cite journal |vauthors=Boyland E, Chasseaud LF | title = The role of glutathione and glutathione S-transferases in mercapturic acid biosynthesis | journal = Adv. Enzymol. Relat. Areas Mol. Biol. | volume = 32 | pages = 173–219 | year = 1969 | pmid = 4892500 | doi = 10.1002/9780470122778.ch5 | series = Advances in Enzymology – and Related Areas of Molecular Biology | isbn = 9780470122778 }}</ref> Here, the [[glutamic acid|γ-glutamate]] and [[glycine]] residues in the glutathione molecule are removed by [[gamma-glutamyl transpeptidase]] and [[dipeptidase]]s. In the final step, the [[cysteine]] residue in the conjugate is [[acetylated]].

Conjugates and their metabolites can be excreted from cells in phase III of their metabolism, with the anionic groups acting as affinity tags for a variety of membrane transporters of the [[P-glycoprotein|multidrug resistance protein]] (MRP) family.<ref name="pmid12897433">{{cite journal |vauthors=Homolya L, Váradi A, Sarkadi B | title = Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate | journal = BioFactors | volume = 17 | issue = 1–4 | pages = 103–14 | year = 2003 | pmid = 12897433 | doi = 10.1002/biof.5520170111 | s2cid = 7744924 }}</ref> These proteins are members of the family of [[ATP-binding cassette transporter]]s and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions,<ref name="pmid10581368">{{cite journal |vauthors=König J, Nies AT, Cui Y, Leier I, Keppler D | title = Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance | journal = Biochim. Biophys. Acta | volume = 1461 | issue = 2 | pages = 377–94 |date=December 1999 | pmid = 10581368 | doi = 10.1016/S0005-2736(99)00169-8 | doi-access = free }}</ref> and thus act to remove phase II products to the extracellular medium, where they may be further metabolized or excreted.<ref name="pmid7568330">{{cite journal |vauthors=Commandeur JN, Stijntjes GJ, Vermeulen NP | title = Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role in bioactivation and detoxication mechanisms of xenobiotics | journal = Pharmacol. Rev. | volume = 47 | issue = 2 | pages = 271–330 |date=June 1995 | pmid = 7568330 }}</ref>

== Endogenous toxins ==

The detoxification of endogenous reactive metabolites such as [[peroxide]]s and reactive [[aldehyde]]s often cannot be achieved by the system described above. This is the result of these species' being derived from normal cellular constituents and usually sharing their polar characteristics. However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them. The similarity of these molecules to useful metabolites therefore means that different detoxification enzymes are usually required for the metabolism of each group of endogenous toxins. Examples of these specific detoxification systems are the [[glyoxalase system]], which acts to dispose of the reactive aldehyde [[methylglyoxal]], and the various [[antioxidant]] systems that remove [[reactive oxygen species]].

== Sites ==

Quantitatively, the [[smooth endoplasmic reticulum]] of the [[liver]] cell is the principal organ of drug metabolism, although every [[biological tissue]] has some ability to metabolize drugs.
Factors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the [[Gut (zoology)|gut]], and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs.
If a drug is taken into the GI tract, where it enters hepatic circulation through the [[portal vein]], it becomes well-metabolized and is said to show the ''[[first pass effect]]''.

Other sites of drug metabolism include [[epithelial cell]]s of the [[gastrointestinal tract]], [[lung]]s, [[kidney]]s, and the [[skin]].
These sites are usually responsible for localized toxicity reactions.

== Factors that affect drug metabolism ==

The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products.
The [[Cytochrome P450 monooxygenase system]] is the most important pathway in this regard.
In general, anything that ''increases'' the rate of metabolism (''e.g.'', [[Enzyme induction and inhibition|enzyme induction]]) of a pharmacologically active metabolite will ''decrease'' the duration and intensity of the drug action.
The opposite is also true (''e.g.'', [[Enzyme induction and inhibition|enzyme inhibition]]). However, in cases where an enzyme is responsible for metabolizing a pro-drug into a drug, enzyme induction can speed up this conversion and increase drug levels, potentially causing toxicity.

Various ''physiological'' and ''pathological'' factors can also affect drug metabolism.
Physiological factors that can influence drug metabolism include age, individual variation (''e.g.'', [[pharmacogenetics]]), [[enterohepatic circulation]], [[nutrition]], [[intestinal flora]], or [[sex difference]]s.

In general, drugs are metabolized more slowly in [[fetal]], [[neonatal]] and [[elderly]] [[human]]s and [[animal]]s than in [[adult]]s.

Genetic variation ([[Polymorphism (biology)|polymorphism]]) accounts for some of the variability in the effect of drugs.
With N-acetyltransferases (involved in ''Phase II'' reactions), individual variation creates a group of people who acetylate slowly (''slow acetylators'') and those who acetylate quickly, split roughly 50:50 in the population of Canada.
This variation may have dramatic consequences, as the [[N-acetyltransferase#Importance_in_Humans|slow acetylators]] are more prone to dose-dependent toxicity.

[[Cytochrome P450 monooxygenase system]] enzymes can also vary across individuals, with deficiencies occurring in 1–30% of people, depending on their ethnic background.

Dose, frequency, route of administration, tissue distribution and protein binding of the drug affect its metabolism.

''Pathological factors'' can also influence drug metabolism, including [[liver]], [[kidney]], or [[heart]] diseases.

''In silico'' modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects.<ref name="pmid17268485">{{cite journal |vauthors=Rostami-Hodjegan A, Tucker GT | title = Simulation and prediction of in vivo drug metabolism in human populations from ''in vitro'' data | journal = Nat Rev Drug Discov | volume = 6 | issue = 2 | pages = 140–8 |date=February 2007 | pmid = 17268485 | doi = 10.1038/nrd2173 | s2cid = 205476485 }}</ref> This can be used to identify individuals most at risk from adverse reaction.

== History ==

Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as [[benzaldehyde]] could be oxidized and conjugated to amino acids in the human body.<ref name="pmid11353742">{{cite journal | author = Murphy PJ | title = Xenobiotic metabolism: a look from the past to the future | journal = Drug Metab. Dispos. | volume = 29 | issue = 6 | pages = 779–80 | date = June 2001 | pmid = 11353742 | url = http://dmd.aspetjournals.org/cgi/content/full/29/6/779 | access-date = 2012-12-29 | archive-date = 2009-06-21 | archive-url = https://web.archive.org/web/20090621230029/http://dmd.aspetjournals.org/cgi/content/full/29/6/779 | url-status = live }}</ref> During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as [[methylation]], [[acetylation]], and [[sulfonation]].

In the early twentieth century, work moved on to the investigation of the enzymes and pathways that were responsible for the production of these metabolites. This field became defined as a separate area of study with the publication by [[Richard Tecwyn Williams|Richard Williams]] of the book ''Detoxication mechanisms'' in 1947.<ref name="pmid6347595">{{cite journal |vauthors=Neuberger A, Smith RL | title = Richard Tecwyn Williams: the man, his work, his impact | journal = Drug Metab. Rev. | volume = 14 | issue = 3 | pages = 559–607 | year = 1983 | pmid = 6347595 | doi = 10.3109/03602538308991399 }}</ref> This modern biochemical research resulted in the identification of glutathione ''S''-transferases in 1961,<ref name="pmid16748905">{{cite journal |vauthors=Booth J, Boyland E, Sims P | title = An enzyme from rat liver catalysing conjugations with glutathione | journal = Biochem. J. | volume = 79 | issue = 3 | pages = 516–24 |date=June 1961 | pmid = 16748905 | pmc = 1205680 | doi = 10.1042/bj0790516}}</ref> followed by the discovery of cytochrome P450s in 1962,<ref name="pmid14482007">{{cite journal | vauthors = Omura T, Sato R | title = A new cytochrome in liver microsomes | journal = J. Biol. Chem. | volume = 237 | pages = 1375–6 | date = April 1962 | issue = 4 | doi = 10.1016/S0021-9258(18)60338-2 | pmid = 14482007 | url = http://www.jbc.org/cgi/reprint/237/4/PC1375 | doi-access = free | access-date = 2012-12-29 | archive-date = 2009-06-21 | archive-url = https://web.archive.org/web/20090621070319/http://www.jbc.org/cgi/reprint/237/4/PC1375 | url-status = live }}</ref> and the realization of their central role in xenobiotic metabolism in 1963.<ref name="pmid14625342">{{cite journal | author = Estabrook RW | title = A passion for P450s (remembrances of the early history of research on cytochrome P450) | journal = Drug Metab. Dispos. | volume = 31 | issue = 12 | pages = 1461–73 |date=December 2003 | pmid = 14625342 | doi = 10.1124/dmd.31.12.1461 }}</ref><ref name="pmid14087340">{{cite journal |vauthors=Estabrook RW, Cooper DY, Rosenthal O | title = The light reversible carbon monoxide inhibition of steroid C-21 hydroxylase system in adrenal cortex | journal = Biochem Z | volume = 338 | pages = 741–55 | year = 1963 | pmid = 14087340 }}</ref>

==See also==
{{cmn|colwidth=30em|
* [[Antioxidant]]
* [[Biodegradation]]
* [[Bioremediation]]
* [[Dose dumping]]
* [[Microbial biodegradation]]
}}

== References ==
{{reflist}}

== Further reading ==
{{Refbegin}}
* {{cite book |vauthors=Parvez H, Reiss C | title = Molecular Responses to Xenobiotics |url=https://archive.org/details/molecularrespons0000unse |url-access=registration | publisher = Elsevier | year=2001 | isbn = 0-345-42277-5 }}
* {{cite book | author = Ioannides C | title = Enzyme Systems That Metabolise Drugs and Other Xenobiotics | publisher=John Wiley and Sons | year = 2001 | isbn = 0-471-89466-4 }}
* {{cite book | author = Richardson M | title = Environmental Xenobiotics | publisher = Taylor & Francis Ltd | year = 1996 | isbn = 0-7484-0399-X}}
* {{cite book | author = Ioannides C | title = Cytochromes P450: Metabolic and Toxicological Aspects | publisher = CRC Press Inc | year = 1996 | isbn = 0-8493-9224-1 }}
* {{cite book | author = Awasthi YC | title = Toxicology of Glutathionine S-transferses | publisher = CRC Press Inc | year = 2006 | isbn = 0-8493-2983-3 }}
{{Refend}}

==External links==
* Databases
** [https://web.archive.org/web/20070713035439/http://www.issx.org/hisintro.html Drug metabolism database]
** [https://web.archive.org/web/20160716081404/http://www.icgeb.org/~p450srv/ Directory of P450-containing Systems]
** [http://umbbd.ethz.ch/ University of Minnesota Biocatalysis/Biodegradation Database]
** [https://web.archive.org/web/20090318041558/http://www.freebase.com/view/en/sporcalc SPORCalc]
* Drug metabolism
** [http://www.ionsource.com/tutorial/metabolism/drug_metabolism.htm Small Molecule Drug Metabolism]
** [https://web.archive.org/web/20070713035439/http://www.issx.org/hisintro.html Drug metabolism portal]
* Microbial biodegradation
** [http://www.horizonpress.com/gateway/biodegradation.html Microbial Biodegradation, Bioremediation and Biotransformation]
* History
** {{webarchive |url=https://web.archive.org/web/20070713035439/http://www.issx.org/hisintro.html |date=July 13, 2007 |title=History of Xenobiotic Metabolism }}

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Drug metabolism - Revision history