THE EFFECTS OF DIQUAT AND CIPROFIBRATE ON MESSENGER-RNA EXPRESSION AND CATALYTIC ACTIVITIES OF HEPATIC XENOBIOTIC-METABOLIZING AND ANTIOXIDANT ENZYMES IN RAT-LIVER

被引:44
作者
GALLAGHER, EP [1 ]
BUETLER, TM [1 ]
STAPLETON, PL [1 ]
WANG, CH [1 ]
STAHL, DL [1 ]
EATON, DL [1 ]
机构
[1] UNIV WASHINGTON,DEPT ENVIRONM HLTH,SEATTLE,WA 98195
关键词
D O I
10.1006/taap.1995.1171
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Although the mechanisms responsible for chemically induced oxidative stress are under intense investigation, little is known about the effects of prooxidant chemicals on the expression of drug-metabolizing enzymes. We examined the effects of diquat (0.1 mmol/kg, ip) and ciprofibrate (0.025% w/w, diet), chemicals which induce oxidative stress via different biochemical mechanisms, on the steady-state messenger RNA (mRNA) levels of six cytochrome P450 enzymes, seven glutathione S-transferase (GST) isoenzymes, UDP-glucuronosyl transferase 1-06 (UGT1*06), gamma-glutamylcysteine synthetase (gamma GCS), NADP(H):quinone oxidoreductase (quinone reductase), Cu/Zn superoxide dismutase (SOD), catalase, and 18S ribosomal RNA in the livers of male Sprague-Dawley rats. Effects of chemical treatments on mRNA levels were compared to changes in catalytic activities for selected enzymes. Ciprofibrate treatment selectively decreased CYP1A2 mRNA expression, whereas both chemicals suppressed CYP3A2 mRNA expression. CYP4A1 mRNA expression and lauric acid hydroxylase activities were induced by ciprofibrate treatment, whereas diquat treatment moderately increased CYP4A1 mRNA levels without affecting lauric acid hydroxylase activities. The steady-state mRNA levels encoding constitutively expressed GST isozymes (Ya1, Ya2, Yb1, Yb2, and Yc1) were decreased by diquat exposure, and the mRNA encoding four of the five constitutively expressed GSTs (Ya1, Ya2, Yb1, and Yc1) were also decreased by ciprofibrate treatment. Nonconstitutively expressed or low constitutively expressed genes (CYP1A1, CYP2B1, CYP2B2, GST Yc2, GST Yf, and UGT1*06) were not induced by exposure to the prooxidants. Changes in isozyme-specific catalytic activities were more consistent with the observed changes in mRNA expression for the GSTs than for the P450s. Both treatments had inhibitory effects on hepatic GSH biosynthesis by decreasing gamma GCS large-subunit mRNA expression, gamma GCS catalytic activities, and hepatic GSH concentrations. Cu/Zn SOD and quinone reductase mRNA levels were increased after ciprofibrate exposure, whereas Cu/Zn SOD mRNA expression was decreased in the diquat-treated animals. The results of this study indicate that diquat and ciprofibrate can decrease the expression profile of a number of phase I, phase II, and antioxidant enzymes and inhibit GSH biosynthesis. These effects may involve the pre-translational loss of hepatic mRNAs, possibly due to accelerated production of reactive oxygen species. (C) 1995 Academic Press, Inc.
引用
收藏
页码:81 / 91
页数:11
相关论文
共 42 条
[1]   MOLECULAR CHARACTERIZATION OF THE SOXRS GENES OF ESCHERICHIA-COLI - 2 GENES CONTROL A SUPEROXIDE STRESS REGULON [J].
AMABILECUEVAS, CF ;
DEMPLE, B .
NUCLEIC ACIDS RESEARCH, 1991, 19 (16) :4479-4484
[2]   IRREVERSIBLE INHIBITION OF HEPATIC GLUTATHIONE S-TRANSFERASE BY CIPROFIBRATE, A PEROXISOME PROLIFERATOR [J].
AWASTHI, YC ;
SINGH, SV ;
GOEL, SK ;
REDDY, JK .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1984, 123 (03) :1012-1018
[3]  
BARKER CW, 1994, J BIOL CHEM, V269, P3985
[4]   INCREASE IN METALLOTHIONEIN PRODUCED BY CHEMICALS THAT INDUCE OXIDATIVE STRESS [J].
BAUMAN, JW ;
LIU, J ;
LIU, YP ;
KLAASSEN, CD .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1991, 110 (02) :347-354
[5]   INCREASE OF NAD(P)H-QUINONE REDUCTASE BY DIETARY ANTIOXIDANTS - POSSIBLE ROLE IN PROTECTION AGAINST CARCINOGENESIS AND TOXICITY [J].
BENSON, AM ;
HUNKELER, MJ ;
TALALAY, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1980, 77 (09) :5216-5220
[6]  
BERGELSON S, 1994, CANCER RES, V54, P36
[7]   MODULATION OF GAMMA-GLUTAMYLCYSTEINE SYNTHETASE LARGE SUBUNIT MESSENGER-RNA EXPRESSION BY BUTYLATED HYDROXYANISOLE [J].
BORROZ, KI ;
BUETLER, TM ;
EATON, DL .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1994, 126 (01) :150-155
[8]  
BUETLER TM, 1995, IN PRESS TOXICOL APP
[9]   THE UDP GLUCURONOSYLTRANSFERASE GENE SUPERFAMILY - SUGGESTED NOMENCLATURE BASED ON EVOLUTIONARY DIVERGENCE [J].
BURCHELL, B ;
NEBERT, DW ;
NELSON, DR ;
BOCK, KW ;
IYANAGI, T ;
JANSEN, PLM ;
LANCET, D ;
MULDER, GJ ;
CHOWDHURY, JR ;
SIEST, G ;
TEPHLY, TR ;
MACKENZIE, PI .
DNA AND CELL BIOLOGY, 1991, 10 (07) :487-494
[10]   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