title: Preferential inhibition of CYP1A enzymes in hepatic microsomes by mexiletine.
abstract: We examined the inhibitory behavior of theophylline oxidations and a variety of cytochrome P450 (P450)-dependent metabolism in the presence of mexiletine (MEX), using hepatic microsomes from both control mice and mice exposed to beta-naphthoflavone (beta-NF). Theophylline metabolism, which is mainly catalyzed by CYP1A2, was susceptible to competitive inhibition by MEX. The calculated inhibition constants (Ki) for theophylline 3-demethylation and its 8-hydroxylation were 4.3 microM and 8.3 microM, respectively, which are comparable to the recommended therapeutic serum range for MEX. The inhibitory potency of MEX on cytochrome P450-dependent enzyme activities diverged among the several metabolic reactions, which were probes for CYP1A, 2A, 2C, 2D, 2E and 3A subfamilies. The Ki value (6.7 microM) for methoxyresorufin O-demethylation mediated by CYP1A2 agreed with those from theophylline oxidations. These metabolic reactions exhibited the smallest Ki values, 1-3 orders of magnitude lower than activities of other constitutive cytochrome P450 species. Similar degrees of inhibition were observed in CYP1A1, a beta-NF-inducible isoform with a relatively high conformity to CYP1A2. These results indicate that MEX acts as a selective and potent inhibitor of the CYP1A enzymes responsible for oxidative biotransformation of chemicals such as theophylline. This evidence provides a fundamental explanation for the pharmacokinetic interactions experienced in clinical practice.
authors.affiliation: Hospital Pharmacy Department, Shiga University of Medical Science, Seta, Ohtsu, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Konishi
authors.forename: K
authors.initials: K
authors.lastname: Morita
authors.forename: T
authors.initials: T
authors.lastname: Minouchi
authors.forename: A
authors.initials: A
authors.lastname: Yamaji
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001667:Binding, Competitive; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008801:Mexiletine / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D013806:Theophylline / Q000378:metabolism*; D019324:beta-Naphthoflavone / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D008801:Mexiletine; D019324:beta-Naphthoflavone; D013806:Theophylline; D019363:Cytochrome P-450 CYP1A1