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

被引:24
作者
Bray, BJ [1 ]
Goodin, MG [1 ]
Inder, RE [1 ]
Rosengren, RJ [1 ]
机构
[1] Univ Otago, Sch Med, Dept Pharmacol, Drug Metab Grp, Dunedin, New Zealand
关键词
paracetamol; retinol; cytochrome P450; hepatotoxicity;
D O I
10.1016/S0278-6915(00)00110-1
中图分类号
TS2 [食品工业];
学科分类号
0832 ;
摘要
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/I; 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. (C) 2001 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:1 / 9
页数:9
相关论文
共 58 条
[11]  
GUENGERICH FP, 1979, MOL PHARMACOL, V15, P154
[12]  
Gupta M P, 1983, Acta Vitaminol Enzymol, V5, P141
[13]  
Haque M, 1998, NUTR REV, V56, P84, DOI 10.1111/j.1753-4887.1998.tb01699.x
[14]   ACETAMINOPHEN NEPHROTOXICITY IN CD-1 MICE .1. EVIDENCE OF A ROLE FOR IN-SITU ACTIVATION IN SELECTIVE COVALENT BINDING AND TOXICITY [J].
HART, SGE ;
BEIERSCHMITT, WP ;
WYAND, DS ;
KHAIRALLAH, EA ;
COHEN, SD .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1994, 126 (02) :267-275
[15]  
HAWKE RL, 1985, MOL PHARMACOL, V28, P283
[16]  
Hoglen NC, 1997, LIVER, V17, P157
[17]   GENDER-RELATED DIFFERENCES IN SUSCEPTIBILITY TO ACETAMINOPHEN-INDUCED PROTEIN ARYLATION AND NEPHROTOXICITY IN THE CD-1 MOUSE [J].
HOIVIK, DJ ;
MANAUTOU, JE ;
TVEIT, A ;
HART, SGE ;
KHAIRALLAH, EA ;
COHEN, SD .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1995, 130 (02) :257-271
[18]   Role of cytochrome P4502E1 in retinol's attenuation of carbon tetrachloride-induced hepatotoxicity in the Swiss Webster mouse [J].
Inder, RE ;
Bray, BJ ;
Sipes, IG ;
Rosengren, RJ .
TOXICOLOGICAL SCIENCES, 1999, 52 (01) :130-139
[19]   PHENYLPROPANOLAMINE POTENTIATION OF ACETAMINOPHEN-INDUCED HEPATOTOXICITY - EVIDENCE FOR A GLUTATHIONE-DEPENDENT MECHANISM [J].
JAMES, RC ;
HARBISON, RD ;
ROBERTS, SM .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1993, 118 (02) :159-168
[20]  
KIM SG, 1993, J PHARM EXPT THERAPE, V246, P1175