Identification of cytochrome P4503A as the major enzyme sub-family responsible for the metabolism of 22,23-dihydro-13-O-[(2-methoxyethoxy)methyl]-avermectin B1 aglycone by rat liver microsomes.
1. Metabolism of 22,23-dihydro-13-O-[(2-methoxyethoxy)methyl]-avermectin B1 aglycone (MEM-H2B1), a new avermectin, by rat liver microsomes has been studied. Metabolites identified were formed by demethylation of the methoxyethoxymethoxy (MEM) side chain, loss of the MEM side chain, partial cleavage and further oxidation of the MEM side chain, and oxidation of the aglycone after cleavage of the MEM side chain. 2. The specific cytochrome P450 isoforms involved in the metabolism of MEM-H2B1 were identified through immunoinhibition studies. Among several antibodies prepared against various cytochrome P450s, only anti-rat P4503A IgG inhibited MEM-H2B1 metabolism by liver microsomes from the untreated rat. Moreover, troleandomycin, a selective suicide inhibitor for enzymes of the cytochrome P4503A family, inhibited the total metabolism by > 80%. These results clearly indicate that cytochrome P4503A is primarily responsible for the metabolism of MEM-H2B1. 3. Secondary metabolism was evident in the metabolism of MEM-H2B1 by dexamethasone and phenobarbital induced liver microsomes, where different isoform(s) of cytochrome P4503A could be involved in these multiple step reactions.
Zeng
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Merck Research Laboratories, Department of Drug Metabolism, Merck & Co., Inc., Rahway, NJ 07065, USA.
Andrew
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Halley
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BA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
C110477:22,23-dihydro-13-O-((2-methoxyethoxy)-methyl)abamectin B(1b) aglycone; C110476:22,23-dihydro-13-O-((2-methoxyethoxy)methyl)abamectin B(1a) aglycone; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007559:Ivermectin; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating