Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2

Abstract

Human CYP1A2 is one of the major CYPs in human liver and metabolizes a variety of clinically important drugs (e.g., clozapine, tacrine, tizanidine, and theophylline), a number of procarcinogens (e.g. benzo[a]pyrene and aflatoxin B(1)), and several important endogenous compounds (e.g. steroids and arachidonic acids). Like many of other CYPs, CYP1A2 is subject to induction and inhibition by a number of compounds, which may provide an explanation for some drug interactions observed in clinical practice. A large interindividual variability in the expression and activity of CYP1A2 and elimination of drugs that are mainly metabolized by CYP1A2 has been observed, which is largely caused by genetic (e.g., SNPs) and epigenetic (e.g., DNA methylation) and environmental factors (e.g., smoking and comedication). CYP1A2 is primarily regulated by the aromatic hydrocarbon receptor (AhR) and CYP1A2 is induced through AhR-mediated transactivation following ligand binding and nuclear translocation. To date, more than 15 variant alleles and a series of subvariants of the CYP1A2 gene have been identified and some of they have been associated with altered drug clearance and response to drug therapy. For example, lack of response to clozapine therapy due to low plasma drug levels has been reported in smokers harboring the -163A/A genotype; there is an association between CYP1A2*1F (-163C>A) allele and the risk for leflunomide-induced host toxicity. The *1F allele is associated with increased enzyme inducibility whereas *1C causes reduced inducibility. Further studies are warranted to explore the clinical and toxicological significance of altered CYP1A2 expression and activity caused by genetic, epigenetic, and environmental factors.

Fig. 1

The structures of human CYP1A2 in complex with ANF (PDB ID = 2HI4; a and c) or caffeine b. The distance from the metabolic site of caffeine to the heme is 4.34 Å

Fig. 2

The docking of two substrates (amitriptyline and naproxen) and two competitive inhibitors (ciprofloxacin and methoxsalen) into the active site of CYP1A2 (PDB ID = 2HI4). The distance from the site of metabolism of amitriptyline and naproxen to the heme group is 4.73 and 3.22 Å, respectively

Fig. 3

A schematic illustration of the aromatic hydrocarbon receptor (AhR)-mediated induction of phase I and phase II drug metabolizing enzymes and drug transporters such as human CYP1A1, 1B1, 1A2, and 2S1, UGT1A1 and 1A6, and MDR1/ABCB1. The AhR exists as cytoplasmic aggregates bound to two 90-kDa heat-shock proteins (Hsps), the cochaperone p23 and a 43-kDa immunophilin-like protein hepatitis B virus X-associated protein 2 (XAP2). Upon binding a ligand, after the replacement of its associated molecule with AhR nuclear translocator (Arnt) to form a heterodimer with release of 90-kDa heat-shock proteins, AhR translocates into the nucleus. This heterodimer interacts with a 5′-GCGTG-3′ DNA sequence, the core binding motif of the xenobiotic response element (XRE) or dioxin response element of the target genes encoding CYP1A1, 1B1, 1A2, and 2S1, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and UGT1A6

Fig. 4

Important alleles of CYP1A2 in humans