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 (CCl 4)-initiated lipid peroxidation in rat-liver microsomes, with the order of efficacy THII > DHII = butylated hydroxytoluene (BHT) ⪢ I-3-C. Each of the indole compounds protected isolated rat hepatocytes against toxicity by CCl 4, N-methyl- N′-nitro- N-nitrosoguanidine and methylmethanesulphonate ( THII ⋍ DHII ⪢ I-3-C ). In vivo administration of the indole compounds 1 hr before treatment with CCl 4 protected against hepatotoxicity (THII > DHII > I-3-C). For the enzyme induction studies, phenobarbital and β-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 NMDA-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, CCl 4-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.