title: N-oxidation of irsogladine by the CYP2C subfamily in the rat, dog, monkey and man.
abstract: 1. The metabolism of irsogladine (ISG) was studied in hepatic microsomes from the rat, dog, monkey and man, and marked species differences were observed in N-oxidation of ISG. The rank order of the activity of the N-oxidation was shown to be man < monkey < dog < rat. 2. Anti-NADPH-P450 reductase antibody inhibited the formation of the N-oxidized metabolite of ISG (ISG-N-oxide) in hepatic microsomes from rats by 74%. Anti-CYP2C11 antibody also inhibited the formation of ISG-N-oxide in hepatic microsomes from rat by 73%, whereas anti-CYP2E1, 3A2 and 4A1 antibody did not inhibit N-oxidation. Thus, CYP2C11 in the rat is at least partially responsible for the N-oxidation of ISG in the rat. 3. Anti-CYP2C11 antibody also inhibited the formation of ISG-N-oxide in hepatic microsomes from the dog and monkey by 61 and 46% respectively. Therefore, a isoform(s) similar to CYP2C11 partially contributed to the N-oxidation of ISG in the dog and monkey. In contrast, human CYP2C9, a member of the human CYP2C subfamily, did not catalyse the N-oxidation of ISG. 4. These findings show that the marked species difference in the N-oxidation of ISG is caused by the difference in the catalytic properties of CYP2C among the species examined.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd, Kyoto, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Hirota
authors.forename: A
authors.initials: A
authors.lastname: Morino
authors.forename: T
authors.initials: T
authors.lastname: Shimada
authors.forename: T
authors.initials: T
authors.lastname: Uematsu
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D000906:Antibodies / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004285:Dogs; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008214:Lymphocytes / Q000201:enzymology; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000276:immunology / Q000378:metabolism*; D014227:Triazines / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000897:Anti-Ulcer Agents; D000906:Antibodies; D007527:Isoenzymes; D014227:Triazines; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase; C041836:irsogladine