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Review
. 2021 Jun 22;11(3):94-114.
doi: 10.3390/jox11030007.

The Central Role of Cytochrome P450 in Xenobiotic Metabolism-A Brief Review on a Fascinating Enzyme Family

Francisco Esteves  1 , José Rueff  1 , Michel Kranendonk  1
Affiliations
Review

The Central Role of Cytochrome P450 in Xenobiotic Metabolism-A Brief Review on a Fascinating Enzyme Family

Francisco Esteves et al. J Xenobiot. .

Abstract

Human Cytochrome P450 (CYP) enzymes constitute a superfamily of membrane-bound hemoproteins that are responsible for the metabolism of a wide variety of clinically, physiologically, and toxicologically important compounds. These heme-thiolate monooxygenases play a pivotal role in the detoxification of xenobiotics, participating in the metabolism of many structurally diverge compounds. This short-review is intended to provide a summary on the major roles of CYPs in Phase I xenobiotic metabolism. The manuscript is focused on eight main topics that include the most relevant aspects of past and current CYP research. Initially, (I) a general overview of the main aspects of absorption, distribution, metabolism, and excretion (ADME) of xenobiotics are presented. This is followed by (II) a background overview on major achievements in the past of the CYP research field. (III) Classification and nomenclature of CYPs is briefly reviewed, followed by (IV) a summary description on CYP's location and function in mammals. Subsequently, (V) the physiological relevance of CYP as the cornerstone of Phase I xenobiotic metabolism is highlighted, followed by (VI) reviewing both genetic determinants and (VI) nongenetic factors in CYP function and activity. The last topic of the review (VIII) is focused on the current challenges of the CYP research field.

Keywords: Cytochrome P450 (CYP); adverse drug reactions (ADRs); carcinogens; drug-metabolizing enzymes (DMEs); metabolism; toxicology; xenobiotic.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Xenobiotic metabolism in the hepatocyte and the central role of CYPs in biotransformation. Besides hydroxylation, exemplified here, CYPs catalyze a variety of other biotransformation reactions (e.g., epoxidation, dealkylation, oxygenation, dehydrogenation, dehalogenation, among others). Non-CYP mediated metabolism may also occur in Phase I via flavin-containing monooxygenases (FMOs), NAD(P)H:quinone oxidoreductases (NQOs), amine oxidases, alcohol dehydrogenases, esterases and peroxidases. ABC: ATP binding cassette (e.g., multidrug resistance protein family—MRP); GA: glucuronic acid; GSH: glutathione; NTCP: sodium taurocholate cotransporting polypeptide; OAT: organic anion transporters; OATP: organic anion transporting polypeptides; OH: hydroxyl; PAPS: phosphoadenosine-phosphosulfate; SLC: solute carrier transporters; UDPGA: uridine diphosphate-glucuronic acid. Transferases: glutathione S-transferases (GST), methyltransferases, glycine N-acyltransferase (GLYAT), N-acetyltransferases (NAT), sulfotransferases (SULT), UDP-glucuronosyltransferases (UGT).
Figure 2
Figure 2
Examples of reactions catalyzed by CYPs. (A) CYP-mediated bioactivation of thalidomide. (B) CYP-mediated hydroxylation of phenol. (C) CYP-mediated metabolism of caffeine, with multiple metabolites. (D) Bioactivation of benzo[a]pyrene mediated by CYP enzymes. (E) CYP-mediated metabolism of paracetamol and its potential toxicity. (F) CYP-mediated bioactivation of NNK. (G) Bioactivation of aflatoxin B1 by CYP enzymes. AFB1: Aflatoxin B1. APAP: acetaminophen; B[a]P: benzo[a]pyrene; BPDE: benzo[a]pyrene diol epoxide; DMX: dimethylxanthine; GST: glutathione S-transferases; NAPQI: N-acetyl-p-benzoquinone imine; NNAL: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; NNK: nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PST: phenol sulfotransferase; SULT: sulfotransferases; TMX: trimethylxanthine; UGT: UDP-glucuronosyltransferases.
Figure 2
Figure 2
Examples of reactions catalyzed by CYPs. (A) CYP-mediated bioactivation of thalidomide. (B) CYP-mediated hydroxylation of phenol. (C) CYP-mediated metabolism of caffeine, with multiple metabolites. (D) Bioactivation of benzo[a]pyrene mediated by CYP enzymes. (E) CYP-mediated metabolism of paracetamol and its potential toxicity. (F) CYP-mediated bioactivation of NNK. (G) Bioactivation of aflatoxin B1 by CYP enzymes. AFB1: Aflatoxin B1. APAP: acetaminophen; B[a]P: benzo[a]pyrene; BPDE: benzo[a]pyrene diol epoxide; DMX: dimethylxanthine; GST: glutathione S-transferases; NAPQI: N-acetyl-p-benzoquinone imine; NNAL: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; NNK: nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PST: phenol sulfotransferase; SULT: sulfotransferases; TMX: trimethylxanthine; UGT: UDP-glucuronosyltransferases.
Figure 2
Figure 2
Examples of reactions catalyzed by CYPs. (A) CYP-mediated bioactivation of thalidomide. (B) CYP-mediated hydroxylation of phenol. (C) CYP-mediated metabolism of caffeine, with multiple metabolites. (D) Bioactivation of benzo[a]pyrene mediated by CYP enzymes. (E) CYP-mediated metabolism of paracetamol and its potential toxicity. (F) CYP-mediated bioactivation of NNK. (G) Bioactivation of aflatoxin B1 by CYP enzymes. AFB1: Aflatoxin B1. APAP: acetaminophen; B[a]P: benzo[a]pyrene; BPDE: benzo[a]pyrene diol epoxide; DMX: dimethylxanthine; GST: glutathione S-transferases; NAPQI: N-acetyl-p-benzoquinone imine; NNAL: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; NNK: nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PST: phenol sulfotransferase; SULT: sulfotransferases; TMX: trimethylxanthine; UGT: UDP-glucuronosyltransferases.
Figure 3
Figure 3
Schematic representation of the nomenclature system of CYP genes (example of CYP3A4*1).
Figure 4
Figure 4
Factors influencing inter- and intra-individual variability in CYP activity and expression, and their impact on xenobiotic metabolism (CYP circles: size indicate the importance of the different inter- and intra-individual levels of expression and function of CYP enzymes).
Figure 5
Figure 5
Main mechanisms of CYP induction. AhR: aryl hydrocarbon receptor; CAR: constitutive androstane receptor; CLEM4: constitutive liver enhancer module 4; DR4: direct repeat 4; ER8: estrogen receptor 8; HNF4α: hepatocyte nuclear factor 4α; PBREM: phenobarbital-responsive enhancer module; PPAR: proliferator-activated receptor; prPXRE: proximal PXR responsive element; PXR: pregnane nuclear receptor; XNR: xenobiotic-nuclear receptors; XNR-RE: xenobiotic-nuclear receptors-responsive elements; XREM: xenobiotics-responsive enhancer module. (Note: other regulatory factors and elements not referred may be involved in CYP expression induction).
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