The effect of retinol on hepatic and renal drug-metabolising enzymes

Retinol pretreatment (75 mg/kg/day, 4 days) potentiated paracetamol-induced hepatotoxicity in BALB/c mice (alanine aminotransferase (ALT) activity; 25 10 +/- 602 vs 1155 +/- 282 IU/I; retinol + paracetamol vs corn oil + parace tamol, respectively, P < 0.05); however, this potentiation did not occur in the kidney, indicating an organ-specific response. Retinol treatment alone was not toxic in either organ, as indicated by ALT activity, blood urea ni trogen and creatinine. The potentiation effect could be mediated by retinol 's induction of CYP450 isoforms relevant to paracetamol metabolism or throu gh depletion of glutathione. Therefore, these parameters were investigated in both organs. Following retinol treatment, renal CYP2E1 and hepatic CYP1A 2 and CYP2E1 catalytic activities and polypeptide levels were unchanged. Ho wever, retinol significantly decreased both the catalytic activity (0.23 +/ - 0.03 vs 0.53 +/- 0.06 nmol/mg/min; retinol vs untreated, respectively, P < 0.05) and polypeptide levels (58 +/- 0.6% of control) of hepatic CYP3A. I nhibition of renal CYP3A did not occur as catalytic activity and polypeptid e levels were unchanged from control. Following retinol treatment, total re duced glutathione levels, in both organs, were not significantly different from control. Therefore, the potentiation of paracetamol-induced hepatotoxi city is independent of CYP450 and glutathione. (C) 2001 Elsevier Science Lt d. All rights reserved.