title: Role of specific cytochrome P450 enzymes in the N-oxidation of the antiarrhythmic agent mexiletine.
abstract: 1. Mexiletine is extensively metabolized in man by C- and N-oxidation and the aim of the present study was to characterize major cytochrome P450 enzyme(s) involved in the formation of N-hydroxymexiletine. 2. Incubations with genetically engineered microsomes indicated that the formation rate of N-hydroxymexiletine was highest in the presence of microsomes expressing high levels of either CYP1A2 or CYP2E1 and the formation of N-hydroxymexiletine by human liver microsomes was inhibited about 40% by antibodies directed against CYP1A1/1A2 or CYP2E1. Additional incubations demonstrated that formation of N-hydroxymexiletine was decreased 47 and 51% by furafylline, 40 microm and 120 microm, respectively, and decreased 55 and 67% by alpha-naphthoflavone, 1 microm and 3 microm, respectively (all p < 0.05 versus control). 3. The formation rate of N-hydroxymexiletine in human liver microsomes was highly correlated with CYP2B6 (RS-mexiletine, r = 0.7827; R-(-)-enantiomer, r = 0.7034; S-(+)-enantiomer, r = 0.7495), CYP2E1 (S-(+)-enantiomer, r = 0.7057) and CYP1A2 (RS-mexiletine, r = 0.5334; S-(+)-enantiomer, r = 0.6035). 4. In conclusion, we have demonstrated that CYP1A2 is a major human cytochrome P450 enzyme involved in the formation of N-hydroxymexiletine. However, other cytochrome P450 enzymes (CYP2E1 and CYP2B6) also appear to play a role in the N-oxidation of this drug.
authors.affiliation: Québec Heart Institute, Laval Hospital, Ste-Foy, Québec, Canada G1K 7P4.
authors.forename: L
authors.initials: L
authors.lastname: Labbé
authors.forename: Z
authors.initials: Z
authors.lastname: Abolfathi
authors.forename: E
authors.initials: E
authors.lastname: Lessard
authors.forename: H
authors.initials: H
authors.lastname: Pakdel
authors.forename: P
authors.initials: P
authors.lastname: Beaune
authors.forename: J
authors.initials: J
authors.lastname: Turgeon
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D001571:Benzoflavones / Q000378:metabolism; D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008801:Mexiletine / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology; D008930:Mitochondria, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D008801:Mexiletine; D009249:NADP; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; C050131:furafylline; D006899:Mixed Function Oxygenases