Role of cytochrome P450 in hydrazine toxicity in isolated hepatocytes in vitro.
1. Hepatocytes, isolated from the control, diethyldithiocarbamate (DEDC), acetone, isoniazed and hydrazine pretreated rat, were incubated with hydrazine (8-20 mM) for 3 h. Hydrazine caused a dose-dependent loss of viability, leakage of LDH, depletion of GSH and ATP and an inhibition of the incorporation of 3H-leucine into protein. 2. Pretreatment with DEDC increased, whereas hydrazine and acetone pretreatments decreased the cytoxicity and biochemical effects of hydrazine. Pretreatment with isoniazid slightly increased hydrazine cytotoxicity. Acetone pretreatment reduced the inhibition of protein synthesis caused by hydrazine compared to the control. 3. 4-Nitrophenol hydroxylase activity (P4502E1) correlated with viability, LDH leakage, ATP and GSH depletion in cells from the control, DEDC, acetone and hydrazine pretreated rats. 4. The activities of PROD (P4502B1) and EROD (P4501A1/1A2) also correlated with the above parameters for all treatments. The results suggest that three isoenzymes may be involved in the detoxication of hydrazine. Protein synthesis inhibition did not correlate with the activities of any of the enzymes measured.
Delaney
J
J
Toxicology Department, School of Pharmacy, University of London, UK.
Timbrell
J A
JA
D000096:Acetone / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism / Q000502:physiology*; D004050:Ditiocarb / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006834:Hydrazines / Q000633:toxicity*; D007527:Isoenzymes / Q000502:physiology*; D007538:Isoniazid / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008107:Liver Diseases / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D006834:Hydrazines; D007527:Isoenzymes; D000096:Acetone; C029424:hydrazine; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D007770:L-Lactate Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D005978:Glutathione; D007538:Isoniazid