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Molecular mechanism for alkyl sulfide-modulated carbon tetrachloride-induced hepatotoxicity: the role of cytochrome P450 2E1, P450 2B and glutathione S-transferase expression

Molecular mechanism for alkyl sulfide-modulated carbon tetrachloride-induced hepatotoxicity: the role of cytochrome P450 2E1, P450 2B and glutathione S-transferase expression

Journal of Pharmacology and Experimental Therapeutics 277(2): 1058-1066

The modulation of CC-4-induced hepatotoxicity in response to alkyl sulfides and alkyl ethers including allyl disulfide (ADS), allyl sulfide (AS), allyl ether (AE), propyl disulfide (PDS), propyl sulfide (PS), propyl ether (PE) and butyl sulfide (BS) was studied. Whereas pretreatment of rats with either ADS or AS (50 mg/kg, 7 days) blocked a CCl-4-induced increase in plasma alanine aminotransferase (ALT) activity by 91 and 56%, respectively, AE, PDS, PS, PE or BS treatment enhanced CCl-4-induced ALT activity by 52, 55, 238, 25 or 86%, respectively. Histochemical examinations supported the results of plasma ALT activity. Injection of GdCl-3 to PS-pretreated rats failed to block the potentiated ALT increase, whereas GdCl-3 completely prevented vitamin A-enhanced elevation of ALT activity. AS treatment completely blocked PS-potentiated CCI, intoxication. Concomitant treatment of animals with both PS and vitamin A followed by a CCl-4, insult resulted in super-potentiation of CCl-4-induced hepatotoxicity, suggesting that the mechanism of PS-enhanced hepatotoxicity differs from that caused by vitamin A. Pyridine or phenobarbital potentiation of CCl-4-induced increases in ALT activity implys that cytochrome P450 2El (P450 2E1) and P450 2B expression may be associated with the increased toxicity. P450 2El expression appeared to be associated with the alkyl sulfide-modulated hepatotoxicity, as evidenced by both immunoblot analyses and metabolic activity. P450 2B immunoblot analysis revealed that either AS or PS substantially induced hepatic P450 2B1/2 levels. Thus, PS-enhanced CCl-4 hepatotoxicity may be related in part with P450 2B induction. ADS, AS or PS treatment caused increases in the glutathione S-transferase (GST) conjugating activity toward 1 -chloro-2,4-dinitro-benzene. ADS, AS or PS induced Ya and Ybl subunits by 2- to 3-fold. ADS or AS treatment also significantly elevated the levels of Yc subunits. PS failed to induce Yc expression, although this agent effectively increased Yb2 expression. Northern blot analyses revealed that ADS and AS concomitantly stimulated GST Ya, Ybl and Yc2 gene expression, whereas PS increased the levels of Ya, Ybl and Yb2 mRNA, but not Yc2 mRNA levels. The expression of GST subunit Yc2 in response to these compounds might be associated with hepatoprotective effects. These results demonstrate that ADS and AS have distinct capability of blocking CCl-4-induced hepatotoxicity, whereas certain saturated alkyl sulfides rather potentiate CCl-4-induced hepatotoxicity and that the underlying mechanism is associated with P450 2E1 and P450 2B expression, and possibly with certain GST expression.

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Accession: 009046020

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PMID: 8627517

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