Biotransformation and detoxification of insecticidal metyrapone analogues by carbonyl reduction in the human liver.
1. The carbonyl reduction of insecticidal metyrapone analogues to their hydroxyl metabolites by human liver microsomes and cytosol was examined. Metabolite quantification was performed by means of hplc determination and inhibition experiments, using specific carbonyl reductase inhibitors, were conducted. 2. The cytotoxicity of the ketones and their hydroxy metabolites was assessed with the MTT test, using Chang liver cells. 3. It was found that the alcohol derivatives are the major metabolite, both in microsomes and cytosol. The microsomal reductive metabolism, considered to be mediated by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) (EC 1.1.1.146), was more extensive than the cytosolic carbonyl reduction. In each case, this metabolism was inhibited significantly by equimolar concentrations of the microsomal 11 beta-HSD inhibitor glycyrrhetinic acid and the cytosolic carbonyl reductase inhibitor quercitrin, respectively. 4. The parent ketones were more cytotoxic than their alcohol metabolites. 5. These results demonstrate that the metyrapone analogues are extensively metabolized by human liver microsomes, presumably by 11 beta-HSD, to the less cytotoxic and readily excretable alcohols. 6. Since the metyrapone analogues can inhibit ecdysone 20-monooxygenase (EC 1.14.99.22), our results indicate potential application of these compounds as insecticides, which would be safer for humans, due to their reductive detoxification, mainly by the hepatic microsomal 11 beta-HSD, to the less toxic hydroxy metabolites.
Rekka
E A
EA
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Greece.
Soldan
M
M
Belai
I
I
Netter
K J
KJ
Maser
E
E
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000438:Alcohols / Q000378:metabolism; D001711:Biotransformation; D003600:Cytosol / Q000201:enzymology; D005260:Female; D006801:Humans; D006900:Hydroxylation; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D008658:Inactivation, Metabolic; D007306:Insecticides / Q000493:pharmacokinetics*; D007659:Ketones / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000648:ultrastructure; D008297:Male; D008797:Metyrapone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000201:enzymology
D000438:Alcohols; D007306:Insecticides; D007659:Ketones; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D008797:Metyrapone