SUPPRESSION OF RAT HEPATIC CYTOCHROME-P450 2E1 EXPRESSION BY ISOPROPYL ENE)-2-[N-(4-METHYL-THIAZOL-2-YL)CARBAMOYL]ACETATE (YH439), AN EXPERIMENTAL HEPATOPROTECTANT - PROTECTIVE ROLE AGAINST HEPATIC-INJURY
Ey. Choi et al., SUPPRESSION OF RAT HEPATIC CYTOCHROME-P450 2E1 EXPRESSION BY ISOPROPYL ENE)-2-[N-(4-METHYL-THIAZOL-2-YL)CARBAMOYL]ACETATE (YH439), AN EXPERIMENTAL HEPATOPROTECTANT - PROTECTIVE ROLE AGAINST HEPATIC-INJURY, Biochemical pharmacology, 52(8), 1996, pp. 1219-1225
The expression of cytochromes P450 2E1, P450 2B and P450 1A was examin
ed in rat hepatic tissue in response to YH439, an experimental hepatop
rotective agent. P450 2E1 metabolic activities relatively specific for
P450 2E1 were decreased up to 57% of control activities in the hepati
c microsomes prepared from rats treated with YH439 for 3 days. Immunob
lot analyses showed that P450 2E1 levels were decreased below the limi
t of detectability in hepatic microsomes prepared from YH439-treated r
ats. YH439 at doses from 25 to 100 mg/kg completely suppressed isoniaz
id-inducible P450 2E1 levels as monitored by both metabolic activities
and immunoblot analysis. RNA hybridization analysis revealed that P45
0 2E1 mRNA levels failed to change after YH439 treatment. These result
s demonstrate the YH439 effectively suppresses P450 2E1 expression in
the absence of transcriptional inactivation. YH439 failed to affect P4
50 2B1/2 expression, whereas this agent enhanced the hepatic P450 1A1/
2 levels. The hepatoprotective effects of YH439 were also examined. An
imals treated with CCl4 and ethanol for 9 weeks showed hepatic injury
as demonstrated by 2.5- and 2-fold increases in serum alanine aminotra
nsferase and alkaline phosphatase activities, respectively. Concomitan
t YH439 treatment resulted in a significant protective effect against
the experimental hepatic injury. The toxicant;induced elevation in hep
atic hydroxyproline level was completely blocked by YH439 treatment. T
hese data indicate that YH439 suppresses the expression of P450 2E1 an
d protects the liver against chemical-induced hepatic injury and that
the selective modulation of detoxifying enzymes by YH439 may contribut
e to the protection of liver from xenobiotic-induced intoxication.