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Modulation of rat hepatic microsomal monooxygenase enzymes and cytotoxicity by diallyl sulfide
J F Brady1, M H Wang, J Y Hong
1Department of Chemical Biology and Pharmacognosy, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08855-0789.
Abstract:
Diallyl sulfide (DAS) and other organosulfur compounds inhibit chemically induced carcinogenic and toxic responses in rodent model systems. A possible mechanism of action is the inhibition of the hepatic cytochrome P450IIE1-dependent bioactivation of the procarcinogens and protoxicants. Previous work showed competitive inhibition by DAS of N-nitrosodimethylamine (NDMA) demethylase activity in vitro, and a reduction in the microsomal level of P450IIE1 after in vivo treatment with DAS. The present studies demonstrated a time- and dose-dependent decrease of hepatic microsomal P450IIE1 activity, induction of P450IIB1 and pentoxyresorufin dealkylase activity, and moderate induction of ethoxyresorufin dealkylase activity by oral DAS treatment. DAS treatment elevated P450IIB1 mRNA but had no effect on P450IIE1 mRNA. Treatment with putative metabolites of DAS, diallyl sulfoxide and diallyl sulfone, led to similar modulations in monooxygenase activities, but the decrease of P450IIE1 activity by the sulfone occurred more rapidly. In studies in vitro, diallyl sulfone caused a metabolism-dependent inactivation of P450IIE1, but such inactivation was not observed with DAS or diallyl sulfoxide. The profile of microsomal testosterone metabolism after DAS treatment indicated an enhancement of P450IIB1-dependent 16 beta-hydroxylase activity, and a decrease in 6 beta-hydroxytestosterone production possibly related to a lower level of P450IIIA1 or IIIA2. When rats were subjected to a 48-hr fast and DAS treatment, the starvation-induced microsomal P450IIE1 level was decreased by DAS. Inhibition of hepatotoxicity due to exposure to P450IIE1 substrates, CCl4 and NDMA, by DAS was observed under a variety of treatment schedules.
Insights
Diallyl sulfide (DAS) reduces harmful chemical activation by inhibiting cytochrome P450IIE1. This organosulfur compound also induces other P450 enzymes, offering protection against chemical toxicity and carcinogenicity in animal models.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Organosulfur compounds, like diallyl sulfide (DAS), show promise in inhibiting chemically induced toxicity and carcinogenicity in animal models.
- A key mechanism involves the inhibition of hepatic cytochrome P450IIE1-mediated bioactivation of procarcinogens and protoxicants.
- Previous studies indicated DAS competitively inhibits N-nitrosodimethylamine (NDMA) demethylase activity and reduces P450IIE1 levels in vivo.
Purpose of the Study:
- To investigate the detailed effects of oral diallyl sulfide (DAS) administration on hepatic microsomal monooxygenase activities and P450 enzyme expression in rodents.
- To explore the role of DAS metabolites, diallyl sulfoxide and diallyl sulfone, in modulating these enzymatic activities.
- To assess the protective effects of DAS against chemical-induced hepatotoxicity.
Main Methods:
- Oral administration of DAS to rats to evaluate time- and dose-dependent effects on P450IIE1, P450IIB1, and pentoxyresorufin/ethoxyresorufin dealkylase activities.
- Analysis of P450IIB1 and P450IIE1 mRNA levels following DAS treatment.
- In vitro studies using DAS and its metabolites (diallyl sulfoxide, diallyl sulfone) to assess their impact on P450IIE1 activity and inactivation.
- Examination of microsomal testosterone metabolism profiles to evaluate P450IIB1 and P450IIIA subfamily activities.
- Investigation of DAS effects on starvation-induced P450IIE1 levels and protection against CCl4 and NDMA-induced hepatotoxicity.
Main Results:
- Oral DAS treatment decreased hepatic microsomal P450IIE1 activity and increased P450IIB1 and pentoxyresorufin dealkylase activities, with moderate induction of ethoxyresorufin dealkylase.
- DAS elevated P450IIB1 mRNA levels but did not affect P450IIE1 mRNA.
- Diallyl sulfone, but not DAS or diallyl sulfoxide, caused metabolism-dependent inactivation of P450IIE1 in vitro.
- DAS treatment enhanced P450IIB1-dependent 16 beta-hydroxylase activity and decreased 6 beta-hydroxytestosterone production, suggesting reduced P450IIIA activity.
- DAS reduced starvation-induced P450IIE1 levels and inhibited hepatotoxicity caused by P450IIE1 substrates like CCl4 and NDMA.
Conclusions:
- Diallyl sulfide modulates hepatic cytochrome P450 enzyme expression and activity, leading to reduced bioactivation of toxic and carcinogenic compounds.
- The observed protective effects against hepatotoxicity are likely mediated by the inhibition of P450IIE1 and potentially other P450 isoforms.
- DAS and its metabolites, particularly diallyl sulfone, represent a promising class of compounds for chemoprevention strategies against chemical-induced toxicity.