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The effect of methimazole on thioamide bioactivation and toxicity
1School of Biochemistry, University of Birmingham, U.K.
Abstract:
The hepatotoxicity induced by administration of ethionamide and thionicotinamide (TNA) was shown to be decreased by pre-administration of methimazole (MMI). Pre-administration of MMI was also shown to decrease the levels of excretion of TNA S-oxide. This indicates that thioamide S-oxidation, mediated by the flavin-containing mono-oxygenase, may be linked to the initiation of hepatotoxicity induced by these thioamides. SK&F-525-A, the cytochrome P-450 inhibitor, did not affect either thioamide-induced toxicity or levels of excretion of TNA S-oxide; however, the role of the P-450 isoenzymes cannot be totally ruled out.
Insights
Methimazole (MMI) reduces liver damage caused by ethionamide and thionicotinamide (TNA). MMI also lowers TNA S-oxide excretion, suggesting S-oxidation by flavin-containing mono-oxygenase is key to thioamide hepatotoxicity.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Thioamides like ethionamide and thionicotinamide (TNA) can cause liver damage (hepatotoxicity).
- The metabolic pathways leading to thioamide-induced hepatotoxicity are not fully understood.
- Flavin-containing mono-oxygenase (FMO) and cytochrome P-450 (CYP450) are key enzymes in drug metabolism.
Purpose of the Study:
- To investigate the role of thioamide S-oxidation in the hepatotoxicity induced by ethionamide and TNA.
- To determine the involvement of flavin-containing mono-oxygenase (FMO) and cytochrome P-450 (CYP450) in thioamide metabolism and toxicity.
Main Methods:
- Administration of ethionamide and TNA to induce hepatotoxicity.
- Pre-treatment with methimazole (MMI), an FMO inhibitor.
- Administration of SK&F-525-A, a CYP450 inhibitor.
- Measurement of thioamide-induced toxicity and excretion levels of TNA S-oxide.
Main Results:
- Pre-administration of MMI significantly decreased hepatotoxicity induced by ethionamide and TNA.
- MMI pre-treatment also reduced the excretion levels of TNA S-oxide.
- SK&F-525-A did not affect thioamide-induced toxicity or TNA S-oxide excretion.
Conclusions:
- Thioamide S-oxidation, likely mediated by FMO, is implicated in the initiation of hepatotoxicity caused by these compounds.
- The findings suggest FMO plays a crucial role in the toxic mechanism of thioamides.
- While CYP450's role is not entirely excluded, FMO appears to be the primary enzyme involved in the S-oxidation pathway leading to toxicity.