SUPPRESSION OF LIVER CYTOCHROME-P450 BY ALPHA-HEDERIN - RELEVANCE TO HEPATOPROTECTION

被引:21
作者
LIU, J
LIU, YP
BULLOCK, P
KLAASSEN, CD
机构
[1] Department of Pharmacology, Toxicology, and Therapeutics, Environmental Health and Occupational Medicine Center, University of Kansas Medical Center, Kansas City
[2] Ocean Chemistry Division, Institution of Ocean Sciences, Sidney, BC. V8L 4B2, P.O. Box 6000
关键词
D O I
10.1006/taap.1995.1175
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
This study was designed to determine the protective effects of alpha-hederin on chemical-induced liver injury in CF-1 mice and to evaluate cytochrome P450 suppression by alpha-hederin as a means of protection. alpha-Hederin pretreatment (30 mu mol/kg, sc x 3 days) protected mice from acetaminophen-, bromobenzene-, carbon tetrachloride-, furosemide-, and thioacetamide-induced liver injury, without affecting the hepatotoxicity of chloroform and dimethylnitrosamine. To examine the role of P450 in hepatoprotection by alpha-hederin, liver microsomes were prepared 24 hr following the last dose of alpha-hederin treatment (10 and 30 mu mol/kg, sc x 3 days). Treatment of mice with alpha-hederin produced a dose-dependent suppression of liver cytochrome P450 (30-50%) and cytochrome b(5) (20-30%) levels, as well as NADPH-cytochrome c reductase activity (15-25%). alpha-Hederin treatment also decreased the activities of P450 enzymes, such as 7-ethoxyresorufin O-dealkylation (65%), 7-pentoxyresorufin O-dealkylation (50%), coumarin 7-hydroxylation (40%), 7-ethoxycoumarin O-deethylation (45%), caffeine N-3-demethylation (30-50%), chlorzoxazone 6-hydroxylation (35-55%), and the oxidation of testosterone to 2 alpha-, 6 alpha-, 15 alpha-, 15 beta-, 16 alpha-, 16 beta-, and 18/12 alpha-hydroxyltestosterone, androstenedione, and 6-dehydroxytestosterone (25-60%). Consistent with these observations, the levels of CYP1A, CYP2A, and CYP3A enzymes were also suppressed, as determined by immunoblotting with antibodies against rat P450 enzymes. These results demonstrate that treatment of mice with alpha-hederin decreases the levels and activities of several P450 enzymes. The suppression of P450 appears to be one of mechanisms by which alpha-hederin protects mice from the hepatotoxicity of some chemicals. (C) 1995 Academic Press, Inc.
引用
收藏
页码:124 / 131
页数:8
相关论文
共 48 条
[1]   PURIFICATION OF 2 ISOZYMES OF RAT-LIVER MICROSOMAL CYTOCHROME-P450 WITH TESTOSTERONE 7-ALPHA-HYDROXYLASE ACTIVITY [J].
ARLOTTO, MP ;
GREENWAY, DJ ;
PARKINSON, A .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1989, 270 (02) :441-457
[2]   REVIEW ON THE GENOTOXIC ACTIVITY OF THIOACETAMIDE [J].
ARNI, P .
MUTATION RESEARCH, 1989, 221 (02) :153-162
[3]   ETHOXYPHENOXAZONES, PENTOXYPHENOXAZONES, AND BENZYLOXYPHENOXAZONES AND HOMOLOGS - A SERIES OF SUBSTRATES TO DISTINGUISH BETWEEN DIFFERENT INDUCED CYTOCHROMES-P-450 [J].
BURKE, MD ;
THOMPSON, S ;
ELCOMBE, CR ;
HALPERT, J ;
HAAPARANTA, T ;
MAYER, RT .
BIOCHEMICAL PHARMACOLOGY, 1985, 34 (18) :3337-3345
[4]   HUMAN CYTOCHROME P-450PA (P-450IA2), THE PHENACETIN O-DEETHYLASE, IS PRIMARILY RESPONSIBLE FOR THE HEPATIC 3-DEMETHYLATION OF CAFFEINE AND N-OXIDATION OF CARCINOGENIC ARYLAMINES - (AROMATIC-AMINES HETEROCYCLIC AMINES CARCINOGEN METABOLISM) [J].
BUTLER, MA ;
IWASAKI, M ;
GUENGERICH, FP ;
KADLUBAR, FF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (20) :7696-7700
[5]   BOTH CYTOCHROMES P450 2E1 AND 1A1 ARE INVOLVED IN THE METABOLISM OF CHLORZOXAZONE [J].
CARRIERE, V ;
GOASDUFF, T ;
RATANASAVANH, D ;
MOREL, F ;
GAUTIER, JC ;
GUILLOUZO, A ;
BEAUNE, P ;
BERTHOU, F .
CHEMICAL RESEARCH IN TOXICOLOGY, 1993, 6 (06) :852-857
[6]  
CORCOS L, 1992, DRUG METAB DISPOS, V20, P797
[7]   THERAPEUTIC EFFECTIVENESS OF CYSTAMINE AND CYSTEINE TO REDUCE LIVER-CELL NECROSIS INDUCED BY SEVERAL HEPATOTOXINS [J].
DEFERREYRA, EC ;
DEFENOS, OM ;
BERNACCHI, AS ;
DECASTRO, CR ;
CASTRO, JA .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1979, 48 (02) :221-228
[9]  
FARBER J L, 1984, Pharmacological Reviews, V36, p71S
[10]  
Guengerich F. P., 1987, MAMMALIAN CYTOCHROME