Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2.
Article Details
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Zhou SF, Yang LP, Zhou ZW, Liu YH, Chan E
Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2.
AAPS J. 2009 Sep;11(3):481-94. doi: 10.1208/s12248-009-9127-y. Epub 2009 Jul 10.
- PubMed ID
- 19590965 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Amitriptyline Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Cinnarizine Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Cyclobenzaprine Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Gatifloxacin Cytochrome P450 1A2 Protein Humans NoInhibitorDetails Moxifloxacin Cytochrome P450 1A2 Protein Humans NoInhibitorDetails Pefloxacin Cytochrome P450 1A2 Protein Humans UnknownInhibitorDetails Pentoxifylline Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Verapamil Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails