Intervention in free radical mediated hepatotoxicity and lipid peroxidation by indole-3-carbinol

Biochem Pharmacol. 1988 Jan 15;37(2):333-8. doi: 10.1016/0006-2952(88)90737-x.

Abstract

The cytoprotective effect of the natural dietary constituent indole-3-carbinol (I-3-C) on carbon tetrachloride (CCl4) mediated hepatotoxicity in mice was examined. I-3-C pretreatment by gavage 1 hr prior to intraperitoneal injection of CCl4 produced a 63% decrease in CCl4-mediated centrolobular necrosis and a related 60% decrease in plasma alanine aminotransferase activity (a marker of liver necrosis). Since the toxicological effects of CCl4 are mediated by radical species generated during reductive metabolism by cytochrome P-450, we examined the potential ability of I-3-C to scavenge reactive radicals. Three systems were used to evaluate the ability of I-3-C to intervene in free radical mediated lipid peroxidation. These systems consisted of the following: (1) phospholipid dissolved in chlorobenzene, with peroxidation initiated by the thermal and photo decomposition of azobisisobutyronitrile (AIBN); (2) sonicated phospholipid vesicles in phosphate buffer (pH 7.4), with peroxidation initiated by ferrous/ascorbate; and (3) mouse liver microsomes containing an NADPH-regenerating system, with peroxidation initiated with CCl4. Lipid peroxidation was measured in these three systems as thiobarbiturate-reacting material. In the AIBN and ferrous/ascorbate systems, I-3-C inhibited lipid peroxidation, with greater inhibition under conditions of low rates of free radical generation. I-3-C was not as effective an antioxidant as butylated hydroxytoluene (BHT) or tocopherol, but it inhibited peroxidation in a dose-response manner. I-3-C was most effective as a radical scavenger in the microsomal CCl4-initiated system by inhibiting lipid peroxidation in a dose-dependent fashion, with 50% inhibition at 35-40 microM I-3-C. This concentration is about one-third of the concentration of I-3-C achieved in liver after treatment of mice by gavage with 50 mg I-3-C/kg body weight. These data suggest that I-3-C may be a natural antioxidant in the human diet and, as such, may intervene in toxicological or carcinogenic processes that are mediated by radical mechanisms.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carbon Radioisotopes
  • Carbon Tetrachloride Poisoning / metabolism
  • Carbon Tetrachloride Poisoning / prevention & control*
  • Free Radicals
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Kinetics
  • Lipid Peroxides / metabolism*
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism

Substances

  • Carbon Radioisotopes
  • Free Radicals
  • Indoles
  • Lipid Peroxides
  • indole-3-carbinol