Zinc ethylene-bis-dithiocarbamate (Zineb)-mediated inhibition of monooxygenases and lipid peroxidation in bovine liver microsomes.
Hepatic bovine microsomes were incubated with Zineb concentrations ranging from 2.5 mM to 2.5 microM. Only the higher concentrations of the fungicide (2.5 and 0.25 mM) elicited a sharp decline in cytochrome P450, cytochrome b5 and total sulphydryl groups content as well as in the activities of NADPH cytochrome c reductase, aminopyrine N-demethylase and aniline 4-hydroxylase. The loss of cytochrome P450 was matched by a concomitant increase in the amount of cytochrome P420, which represents a catalytically inactive form of cytochrome P450. The same concentrations of the fungicide, either alone or in the presence of NADPH 1 mM, failed to increase the amount of thiobarbituric reactive substances with respect to control incubations, thereby excluding the possibility of lipid peroxidation as a contributing factor in the loss of cytochrome P450 and in the inhibition of cytochrome P450-mediated metabolism. It is concluded that Zineb can depress monooxygenase activity in bovine hepatic microsomes mainly through the denaturation of cytochrome P450 and the impaired transfer of reducing equivalents to the complex cytochrome P450-substrate. These mechanisms might also account for the inhibition in lipid peroxidation brought about by the fungicide.
Nebbia
C
C
Department of Animal Pathology, University of Turin, Italy.
Dacasto
M
M
Topi
B
B
Burdino
E
E
Ugazio
G
G
D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors; D000815:Aniline Hydroxylase / Q000037:antagonists & inhibitors; D000818:Animals; D002417:Cattle; D065607:Cytochrome P-450 Enzyme Inhibitors; D003580:Cytochromes / Q000378:metabolism; D015786:Cytochromes b5 / Q000037:antagonists & inhibitors; D005659:Fungicides, Industrial / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors; D013438:Sulfhydryl Compounds / Q000032:analysis; D015038:Zineb / Q000633:toxicity*
D065607:Cytochrome P-450 Enzyme Inhibitors; D003580:Cytochromes; D005659:Fungicides, Industrial; D013438:Sulfhydryl Compounds; D015786:Cytochromes b5; C013464:cytochrome P420; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D015038:Zineb