Suppression of rat hepatic cytochrome P450 2E1 expression by isopropyl 2-(1,3-dithioetane-2-ylidene)-2-[N-(4-methyl-thiazol-2-yl)carbamoyl]acetate (YH439), an experimental hepatoprotectant: Protective role against hepatic injury

Abstract

The expression of cytochromes P450 2E1, P450 2B and P450 1A was examined in rat hepatic tissue in response to YH439, an experimental hepatoprotective agent. P450 2E1 metabolic activities relatively specific for P450 2E1 were decreased up to 57% of control activities in the hepatic microsomes prepared from rats treated with YH439 for 3 days. Immunoblot analyses showed that P450 2E1 levels were decreased below the limit of detectability in hepatic microsomes prepared from YH439-treated rats. YH439 at doses from 25 to 100 mg/kg completely suppressed isoniazid-inducible P450 2E1 levels as monitored by both metabolic activities and immunoblot analysis. RNA hybridization analysis revealed that P450 2E1 mRNA levels failed to change after YH439 treatment. These results demonstrate the YH439 effectively suppresses P450 2E1 expression in the absence of transcriptional inactivation. YH439 failed to affect P450 2B1/2 expression, whereas this agent enhanced the hepatic P450 1A1/2 levels. The hepatoprotective effects of YH439 were also examined. Animals treated with CC1 4 and ethanol for 9 weeks showed hepatic injury as demonstrated by 2.5- and 2-fold increases in serum alanine aminotransferase and alkaline phosphatase activities, respectively. Concomitant YH439 treatment resulted in a significant protective effect against the experimental hepatic injury. The toxicant-induced elevation in hepatic hydroxyproline level was completely blocked by YH439 treatment. These data indicate that YH439 suppresses the expression of P450 2E1 and protects the liver against chemical-induced hepatic injury and that the selective modulation of detoxifying enzymes by YH439 may contribute to the protection of liver from xenobiotic-induced intoxication.