Hepatic microsomal oxidative metabolism of pesticides and other xenobiotics in pregnant CD1 mice

Abstract

Pregnancy-related changes in oxidative metabolism of several xenobiotics including pesticides were examined in the hepatic microsomes of CD, mice. The effect of pregnancy on hepatic microsomal cytochrome P-450~catalyzed substrate oxidation was found to be dependent upon the type of reaction examined. Not all substrates undergoing the same reaction showed identical changes during pregnancy. Those enzyme activities which exhibited a decline in specific activity during pregnancy generally exhibited no change in total hepatic capacity. Enzymes posting no change in specific activity throughout gestation generally showed large increases in total hepatic activity. Phorate S-oxidation was catalyzed by both microsomal flavin-containing monooxygenase (MFMO) and cytochrome P-450. Moreover, there was no pregnancy-related change in either MFMO or total enzymatic (MFMO plus cytochrome P-450) phorate S-oxidation. 6 1985 Academic Press. Inc. MATERIALS AND METHODS Chemicals. Aldrin (recrystallized) was obtained from City Chemical (New York, N.Y.). The pesticides carbaryl, EPN (Oethyl-O-p-nitrophenyl phenylphosphonothioate), nicotine, parathion, and phorate were purchased from Chem Service (West Chester, Pa.), and were of the highest purity available. All other chemicals were of 328 0048-3575185 $3 .OO

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

“…Organophosphates are bioactivated by desulfuration of the phosphorothionate sulfur to produce the oxon, a metabolite that is orders of magnitude more potent in cholinesterase inhibition (Neal & Halpert, 1982;Jokanovic, 2001). FMO-dependent oxidation of the thioether moiety produces the sulfoxide, a pathway that represents detoxication compared to oxon production (Hajjar & Hodgson, 1980Kulkarni & Hodgson, 1984;Osimitz & Kulkarni, 1985;Tynes & Hodgson, 1985b;Kinsler et al, 1988Kinsler et al, , 1990Buronfosse et al, 1995;Hodgson et al, 1998;Usmani et al, 2004). Again, we have found human FMO2 to be very effective at S-oxygenation of the thioether of phorate and disulfoton (Henderson et al, 2004a), as has been previously shown for other FMO enzymes and for the mouse FMO2 (Karoly & Rose, 2001).…”