Role of the microsomal fad-containing monooxygenase in the liver toxicity of thioacetamide S-oxide
1984; Elsevier BV; Volume: 31; Issue: 1 Linguagem: Inglês
10.1016/0300-483x(84)90154-9
ISSN1879-3185
AutoresElisabetta Chieli, G Malvaldi,
Tópico(s)Eicosanoids and Hypertension Pharmacology
ResumoTo 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 induces changes in the kinectics 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.
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