Cytochrome P-450-dependent formation of reactive oxygen radicals: isozyme-specific inhibition of P-450-mediated reduction of oxygen and carbon tetrachloride

Xenobiotica. 1990 Sep;20(9):887-900. doi: 10.3109/00498259009046904.

Abstract

1. Ethanol-inducible P450 IIE1 exhibits a high rate of oxygen consumption and oxidase activity. The enzyme is selectively distributed in the liver centrilobular area, the acinar region specifically destroyed after treatment with P450 IIE1 substrates/inducers such as ethanol, carbon tetrachloride, chloroform, N-nitrosodimethylamine and paracetamol. 2. Twenty substrates and ligands for cytochrome P450 IIB4 and P450 IIE1 were evaluated for their ability to inhibit microsomal and reconstituted NADPH-dependent oxidase activity, and the P450 IIE1-catalysed reduction of carbon tetrachloride to chloroform. Type I ligands and substrates did not inhibit the processes whereas nitrogen-containing compounds such as octylamine, cimetidine, imidazole and tryptamine inhibited NADPH oxidation and H2O2 formation in microsomes from starved and acetone-treated rats by around 50%. 3. Tryptamine, octylamine, isoniazid and p-chloroamphetamine inhibited reconstituted P450 IIE1-dependent oxidase activity with half maximal effects at 14-170 microM. 4. Isoniazid, cimetidine and tryptamine inhibited the P450 IIE1-dependent reduction of carbon tetrachloride, whereas acetone was without effect. 5. The oxygen dependency of microsomal oxidase activity exhibited high-affinity and low-affinity phases, with partial saturation at 20 microM of O2. 6. It is concluded that microsomal oxidase activity takes place at physiological concentrations of O2 and that isozyme-specific type II ligands compete with oxygen or carbon tetrachloride for reduction by P-450 haem.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Tetrachloride / metabolism*
  • Cimetidine / pharmacology
  • Cytochrome P-450 Enzyme System / metabolism*
  • Free Radicals
  • Hydrogen Peroxide / metabolism
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Isoenzymes / metabolism
  • Male
  • Microsomes, Liver / metabolism
  • NADP / metabolism
  • NADPH-Ferrihemoprotein Reductase / metabolism
  • Oxidation-Reduction
  • Oxidoreductases / metabolism
  • Oxygen Consumption / drug effects
  • Rats
  • Rats, Inbred Strains

Substances

  • Free Radicals
  • Imidazoles
  • Isoenzymes
  • NADP
  • imidazole
  • Cimetidine
  • Cytochrome P-450 Enzyme System
  • Hydrogen Peroxide
  • Carbon Tetrachloride
  • Oxidoreductases
  • NADPH-Ferrihemoprotein Reductase