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

Although the mechanisms responsible for chemically induced oxidative s tress are under intense investigation, little is known about the effec ts of prooxidant chemicals on the expression of drug-metabolizing enzy mes. We examined the effects of diquat (0.1 mmol/kg, ip) and ciprofibr ate (0.025% w/w, diet), chemicals which induce oxidative stress via di fferent biochemical mechanisms, on the steady-state messenger RNA (mRN A) levels of six cytochrome P450 enzymes, seven glutathione S-transfer ase (GST) isoenzymes, UDP-glucuronosyl transferase 1-06 (UGT106), gam ma-glutamylcysteine synthetase (gamma GCS), NADP(H):quinone oxidoreduc tase (quinone reductase), Cu/Zn superoxide dismutase (SOD), catalase, and 18S ribosomal RNA in the livers of male Sprague-Dawley rats. Effec ts of chemical treatments on mRNA levels were compared to changes in c atalytic activities for selected enzymes. Ciprofibrate treatment selec tively decreased CYP1A2 mRNA expression, whereas both chemicals suppre ssed CYP3A2 mRNA expression. CYP4A1 mRNA expression and lauric acid hy droxylase activities were induced by ciprofibrate treatment, whereas d iquat treatment moderately increased CYP4A1 mRNA levels without affect ing lauric acid hydroxylase activities. The steady-state mRNA levels e ncoding 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 UGT106) were not induced by exposure to the prooxidants . Changes in isozyme-specific catalytic activities were more consisten t with the observed changes in mRNA expression for the GSTs than for t he P450s. Both treatments had inhibitory effects on hepatic GSH biosyn thesis by decreasing gamma GCS large-subunit mRNA expression, gamma GC S catalytic activities, and hepatic GSH concentrations. Cu/Zn SOD and quinone reductase mRNA levels were increased after ciprofibrate exposu re, whereas Cu/Zn SOD mRNA expression was decreased in the diquat-trea ted animals. The results of this study indicate that diquat and ciprof ibrate can decrease the expression profile of a number of phase I, pha se II, and antioxidant enzymes and inhibit GSH biosynthesis. These eff ects may involve the pre-translational loss of hepatic mRNAs, possibly due to accelerated production of reactive oxygen species. (C) 1995 Ac ademic Press, Inc.