Handbook of metabolic pathways of xenobiotics. Lee PW, Aizawa H, Gan LL, Prakash C, Zhong D, eds. Chichester, West Sussex, UK: John Wiley & Sons, Ltd., 2014 Mar; :125-146
Drug-metabolizing enzymes (DMEs) are a diverse group of enzymes responsible for the metabolism of a vast array of xenobiotics, that is, foreign chemicals humans encounter from the environment, including drugs, environmental carcinogens, and food toxicants. DMEs also metabolize certain endobiotics produced endogenously, such as steroids, prostaglandins, and bile acids. DMEs are so named to reflect the prominent and historical role of the study of drug metabolism in understanding the enzymes. Since the first introduction of drug metabolism as a scientific discipline six decades ago, the studies of DMEs have influenced many aspects of biology and medicine, including drug metabolism, enzymology, pharmacology, toxicology, cancer research, drug development, and risk assessment (A Personal and Historical Perspective on Drug Metabolism). Many DME substrates, either exogenous or endogenous, are toxic to the body if left to accumulate to a certain level. Metabolism of the chemicals by DMEs in general leads to the formation of metabolites with increased water solubility and decreased activity to facilitate detoxification and elimination of the chemicals (Functional Group Biotransformations). As a result, the chemical homeostasis within the cell is maintained in the face of chemical challenges. In certain cases, drug metabolism by DMEs increases the biological activity (e.g., toxicity) of chemicals (Metabolic Activation and Associated Drug Toxicity). Metabolic activation is examplified by the metabolism of the polycyclic aromatic hydrocarbon (PAH) procarcinogen benzo[a]pyrene (B[a]P). Oxygenation of B[a]P by cytochrome P4501A (CYP1A, P4501A) enzymes and hydration by epoxide hydrolase (EH) result in the formation of trans-7,8-diol-9,10-epoxide of B[a]P, an ultimate carcinogen capable of binding covalently to the guanine base of DNA (adduct formation) to cause gene mutations and cancerous transformation of the cell. In aggregates, DMEs determine the efficacy, bioavailability, clearance, and toxicity of therapeutic drugs and environmental carcinogens and toxicants in the body by modulating the biotransformation and pharmacokinetic properties of chemicals. Many DMEs are inducible by substrates. Induction of DMEs generally occurs rapidly and subsides as the substrates are metabolized. In most cases, induction of DMEs accelerates the metabolism and reduces the toxicity and pharmacological activity of chemicals. In some cases, induction enhances chemical toxicity, as in the case of metabolic activation of PAH carcinogens. Induction may also cause undesired drug-drug interactions, if induction of a DME increases the metabolism of a co-administered drug. Induction of DMEs is coordinated by a group of ligand-activated receptor/transcription factors called xenobiotic-activated receptors (XARs). This coupled chemical sensing and transcription by XARs allows fast induction and tight control of DMEs by the substrates. Among the XARs, the aryl hydrocarbon receptor (AhR) mediates the induction of CYP1A and 1B that metabolize therapeutic agents, such as caffeine, phenacetin, melatonin, theophylline, and lidocaine, in addition to PAH carcinogens. A wide range of chemicals activate AhR, including environmental carcinogens B[a]P and 2,3,7,8-tetrachlorodibenzo-p-dioxin, the therapeutic agent omeprazole, and endogenous chemicals indole-3-carbinol, kynurenine, and tryptophan photoproduct 6-formylindolo[3,2-b]carbazole. The antioxidant-activated nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the induction of a number of DMEs including glutathione S-transferase (GST), glucuronosyltransferase (UGT), NQO1, and mEH through a common DNA-binding element called the antioxidant response element.(13,14) The pregnane X receptor (PXR, NR1I2) controls the induction of CYP3A4 by clinical drugs including rifampicin, dexamethasone, and St. John's Wort. The constitutive androstane receptor (CAR, NR1I4) mediates the induction of CYP2B by phenobarbital and 5beta-pregnanedione.CYP3A4 is estimated to metabolize approximately 40-60% of clinical drugs. PXR and CAR together are believed to play a critical role in the regulation of the metabolism of clinical drugs in humans by controlling the induction of CYP3A, CYP2B, and several other DMEs.