Differential induction of hepatic microsomal epoxide hydrolase by alkyl sulphides and alkyl ethers in rat

1. Previous studies have shown that the expression of certain cytochromes P450 and major glutathione S-transferases (GSTs) is differentially modulated by alkyl sulphide treatment. The current study was designed to examine the influence of several alkyl sulphides and alkyl ethers on the induction of hepatic microsomal epoxide hydrolase (mEH) in rat. 2. Northern blot analysis has shown that treatment of rats with allyl disulphide (ADS) or allyl sulphide (AS) (50 mg/kg/day, 7 days) resulted in 5-6-fold increases in mEH mRNA levels, whereas allyl ether failed to stimulate mEH gene expression. Rats treated with propyl disulphide (PDS) or propyl sulphide (PS) exhibited increases in mEH mRNA levels, although the relative increases were less than those produced by ADS or AS. Propyl ether failed to increase hepatic mEH mRNA levels. Immunoblot analyses confirmed that allyl and propyl sulphides induce hepatic mEH protein, with the agents containing allyl moiety being more effective. 3. Treatment of rats with ADS at 100 mg/kg resulted in 9-14-fold increases in mEH mRNA levels at 12 and 24 h post-treatment respectively, whereas AS caused a maximal increase at the 24-h time point. Animals treated with PDS or PS exhibited time-related increases in mEH mRNA levels, resulting in 2-6-fold elevations at 72-h post-treatment. The changes in mEH mRNA levels after ADS or AS treatment appeared to be more rapid than those after PDS or PS. The rank order for increases in mEH mRNA levels was ADS > AS > PS > PDS. The result of immunoblot analysis was consistent with that of Northern blot analysis. 4. Rats treated with isopropyl sulphide (IPS), butyl sulphone, tert-butyl sulphide, sec-butyl sulphide or butyl sulphide (100 mg/kg/day) showed 3-5-fold increases in the mEH mRNA levels at 3 days post-treatment. IPS treatment caused a similar increase in the mRNA level to that of PS, whereas the induction efficacy of PDS was lower than that of PS or IPS. Treatment with butyl sulphone as well as the structural isomers of butyl sulphides caused approximately 3-fold elevations in mEH mRNA levels. 5. These results provide evidence that alkyl sulphides, but not alkyl ethers, are capable of increasing mEH mRNA levels and that the organosulphur compounds with the allyl moiety are more effective in stimulating the mEH gene than are saturated alkyl sulphides. The comparable increase in mEH mRNA by butyl sulphone as well as the necessity of sulphur atom suggests that sulphone metabolites from the alkyl sulphides might be the ultimate inducers of mEH.