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; 2510+/-602 vs 1155+/-282 IU/l; retinol+paracetamol vs corn oil+paracetamol, 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 nitrogen and creatinine. The potentiation effect could be mediated by retinol's induction of CYP450 isoforms relevant to paracetamol metabolism or through depletion of glutathione. Therefore, these parameters were investigated in both organs. Following retinol treatment, renal CYP2E1 and hepatic CYP1A2 and CYP2E1 catalytic activities and polypeptide levels were unchanged. However, 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. Inhibition of renal CYP3A did not occur as catalytic activity and polypeptide levels were unchanged from control. Following retinol treatment, total reduced glutathione levels, in both organs, were not significantly different from control. Therefore, the potentiation of paracetamol-induced hepatotoxicity is independent of CYP450 and glutathione.
Bray
B J
BJ
Department of Pharmacology & The Drug Metabolism Group, University of Otago Medical School, Dunedin, New Zealand.
Goodin
M G
MG
Inder
R E
RE
Rosengren
R J
RJ
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000410:Alanine Transaminase / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009928:Organ Specificity / Q000187:drug effects; D020033:Protein Isoforms; D014801:Vitamin A / Q000627:therapeutic use / Q000633:toxicity*; D003313:Zea mays
D018712:Analgesics, Non-Narcotic; D020033:Protein Isoforms; D014801:Vitamin A; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; D000410:Alanine Transaminase; D005978:Glutathione