Chemoprotective and hepatic enzyme induction properties of indole and indenoindole antioxidants in rats.
Three indole antioxidants were compared for their efficacy to inhibit lipid peroxidation, prevent chemical hepatotoxicity and induce enzyme systems involved in the biotransformation of xenobiotics. The dietary indolyl compound indole-3-carbinol (I-3-C), and the synthetic compounds 5,10-dihydroindeno[1,2-b]-indole (DHII) and 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) inhibited carbon tetrachloride (CCl4)-initiated lipid peroxidation in rat-liver microsomes, with the order of efficacy THII greater than DHII = butylated hydroxytoluene (BHT) much greater than I-3-C. Each of the indole compounds protected isolated rat hepatocytes against toxicity by CCl4, N-methyl-N'-nitro-N-nitrosoguanidine and methylmethanesulphonate (THII congruent to DHII much greater than I-3-C). In vivo administration of the indole compounds 1 hr before treatment with CCl4 protected against hepatotoxicity (THII greater than DHII greater than I-3-C). For the enzyme induction studies, phenobarbital and beta-naphthoflavone were used as standards, with corn-oil vehicle controls. The compounds were administered by gavage at 50 mg/kg body weight/day for 10 days. I-3-C produced increases in levels of hepatic cytochromes P-450 and ethoxyresorufin O-deethylase (EROD) activity, as well as in UDP-glucuronosyl transferase (UDPGT), glutathione S-transferase (GST), glutathione reductase (GSSG-Red) and quinone reductase. I-3-C produced decreased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. DHII produced increases in EROD, UDPGT, GST, GSSG-Red and quinone reductase, with decreases in NDMA-demethylase and GSH-Px activities. The only observed effect of THII was a modest induction of EROD activity. After treatment with the indole compounds for 10 days, I-3-C enhanced, while DHII diminished, CCl4-mediated 24-hr hepatotoxicity in rats. We conclude that DHII and THII are suitable candidates to develop further as potential chemoprotective and therapeutic agents for use in humans to treat disorders involving free radicals. THII has the greater radical scavenging efficacy, whereas DHII has the greater capacity to induce many different antioxidative enzymes.
Shertzer
H G
HG
Department of Environmental Health, University of Cincinnati Medical Center, OH 45267-0056.
Sainsbury
M
M
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000096:biosynthesis / Q000097:blood; D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D002251:Carbon Tetrachloride / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D004790:Enzyme Induction / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009954:Ornithine Carbamoyltransferase / Q000096:biosynthesis / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains
D000975:Antioxidants; D007211:Indoles; C016517:indole-3-carbinol; D002251:Carbon Tetrachloride; D009954:Ornithine Carbamoyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase