Role of the microsomal FAD-containing monooxygenase in the liver toxicity of thioacetamide S-oxide.
To evaluate the different contributions of either microsomal FAD-containing ( FADM ) or cytochrome P-450 dependent monooxygenases in the bioactivation and liver toxicity of thioacetamide-S-oxide ( TASO ) (a proximate metabolite of the liver toxin and carcinogen thioacetamide), this compound: (i) was given to rats pretreated with methimazole (a substrate and inhibitor of FADM ), SKF 525-A (an inhibitor of cytochrome P-450) and cobalt protoporphyrin IX (a synthetic porphyrin which induces a long-lasting depletion of the hepatic cytochrome P-450); and (ii) was added to liver microsomes performing oxidation of model FADM or cytochrome P-450 substrates. Whereas the prior administration of methimazole alleviated the TASO induced liver necrosis, SKF 525-A was almost ineffective. Also pretreatment with cobalt protoporphyrin IX prevented liver necrosis. However, this porphyrin derivative was found to depress both cytochrome P-450 dependent and the FADM dependent biotransformations. On the other hand, addition of TASO to liver microsomes in vitro induced changes in the kinetics of S-oxidation of thiobenzamide and of N-oxidation of dimethylaniline, whereas the O-deethylation of ethoxycoumarin was unchanged. The overall results show the necessity of TASO bioactivation by mixed-function monooxygenases for the toxic action to be apparent; at the same time, the findings suggest FADM as the system mainly involved in TASO metabolism.
D000081:Acetamides / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009336:Necrosis; D010105:Oxygenases / Q000502:physiology*; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013853:Thioacetamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*
D000081:Acetamides; D013853:Thioacetamide; C029188:thioacetamide-S-oxide; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)