Metabolic deactivation of furylfuramide by cytochrome P450 in human and rat liver microsomes.
Metabolic deactivation of furylfuramide by human and rat liver microsomal cytochrome P450 enzymes has been investigated in a system measuring induction of umu gene expression response in Salmonella typhimurium TA1535/pSK1002. Both human and rat liver microsomes catalyzed the metabolism of furylfuramide to inactive form(s) that are incapable of inducing umu gene expression in the tester strain. The reaction required an NADPH-generating system and molecular oxygen and was inhibited by carbon monoxide, suggesting that a cytochrome P450-linked mono-oxygenase system is prerequisite for the deactivation reaction. With liver microsomes from variously pretreated rats, 3-methylcholanthrene was found to be a powerful inducer for the furylfuramide-metabolizing activity, and antibodies raised against rat P450IA1(BNF-B, c) and P450IA2(ISF-G, d) inhibited the microsomal activity. Human liver microsomal furylfuramide-metabolizing activity was also inhibited significantly by anti-P450IA2 IgG but weakly by anti-P450IA1 IgG. In liver microsomes prepared from seven different human samples, the activities of deactivation of furylfuramide were found to correlate with the amounts of immunoreactive protein related to rat P450IA2 and with the monooxygenase activities of metabolic activation of 2-amino-3,4-dimethyl-imidazo[4,5-f]quinoline (MeIQ) and of ethoxyresorufin O-deethylation. These results suggest that P450IA1 and P450IA2 in rats, and P450PA (IA2, the phenacetin O-deethylase and ortholog of rat P450IA2) in humans are the major enzymes involved in the deactivation of furylfuramide in liver microsomes. The metabolic studies involving HPLC analysis of products followed by spectrophotometric examination have also suggested that furylfuramide can be degraded very rapidly through the aerobic metabolism by liver microsomes.
Osaka Prefectural Institute of Public Health, Japan.
T
T
Shimada
H
H
Yamazaki
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H
Shimura
R
R
Tanaka
F P
FP
Guengerich
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005668:Furylfuramide / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008658:Inactivation, Metabolic; D007700:Kinetics; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009152:Mutagenicity Tests; D009369:Neoplasms / Q000378:metabolism; D009581:Nitrofurans / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D012016:Reference Values; D012486:Salmonella typhimurium / Q000187:drug effects; D013053:Spectrophotometry
D001571:Benzoflavones; D009581:Nitrofurans; D005668:Furylfuramide; D008748:Methylcholanthrene; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital