Role of cytochrome P4502E1 in retinol's attenuation of carbon tetrachloride-induced hepatotoxicity in the Swiss Webster mouse

In the mouse, retinol administration attenuates carbon tetrachloride (CCl4) -induced hepatic injury. We have investigated the role of cytochrome P4502E 1 (CYP2E1) in this interaction. Male Swiss Webster mice were administered r etinol (75 mg/kg/d) or vehicle for 3 days prior to CCI4 (30 mu l/kg, ip). H epatotoxicity produced by CCI4 was assessed by plasma alanine aminotransfer ase (ALT) activity and light microscopy (ALT activity of 1391 +/- 430 vs. 2 74 +/- 92 IU/L for vehicle + CCl4 and retinol + CCl4 treatments respectivel y, p < 0.05). Retinol's attenuation of liver injury was maintained when CCl 4 was administered 48 h after the conclusion of the retinol pretreatment. A niline hydroxylation activity, an indicator of CYP2E1 catalytic activity, d etermined on day 4 was 33.8% of untreated control in vehicle + CCI4 treatme nts while the retinol + CCl4 treatment group was 94.2% of untreated control . Additionally, CYP2E1 immunoreactive protein was 78% lower in vehicle + CC l4 vs. retinol + CCl4 treatment groups. Attenuation of potentiated hepatoto xicity was also observed when CYP2E1 was induced by acetone (ALT activity o f 3119 +/- 1066 vs. 247 +/- 77 IU/L for vehicle and retinol treatments resp ectively, p < 0.05). In the mouse, retinol itself does not alter constituti ve or inducible CYP2E1 expression. However, in combination with CCl4 retino l does reduce the amount of CCl4 bioactivated to its toxic metabolite. We c onclude that retinol attenuates CCl4-induced hepatotoxicity by causing a de crease in CCl4 bioactivation but does not cause a decrease in CYP2E1 expres sion.