Toxicology of thiono-sulfur compounds

Annu Rev Pharmacol Toxicol. 1982;22:321-39. doi: 10.1146/annurev.pa.22.040182.001541.

Abstract

Thiono-sulfur-containing compounds cause a wide variety of toxic effects in mammals. These toxic effects of thiono-sulfur-containing compounds appear to be at least partially the result of their metabolism to reactive intermediates by the cytochrome P-450-containing monooxygenase enzyme systems. Covalent binding of (atomic) sulfur released in the cytochrome P-450 monooxygenase catalyzed metabolism of certain thiono-sulfur compounds appears to be responsible for the inhibition of monooxygenase activity and the loss of cytochrome P-450 seen on administration of these thiono-sulfur compounds in vivo or incubation with cytochrome P-450 monooxygenase enzymes in vitro. Liver necrosis and perhaps the induction of lung edema and neoplasia as well as other effects of thiono-sulfur-containing compounds are more likely the result of the covalent binding of the electrophilic S-oxides or S-dioxides or carbene derivatives of these S-oxides and S-dioxides to tissue macromolecules. The rationale for implicating metabolites of thiono-sulfur compounds other than atomic sulfur in these effects derives from the experiments with thioacetamide and the fact that atomic sulfur is highly reactive and appears to bind predominantly or exclusively to cytochrome P-450. It is difficult to rationalize why binding to and inhibition of cytochrome P-450 would lead to the production of, for examples, liver necrosis.

Publication types

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

MeSH terms

  • Animals
  • Antimetabolites / pharmacology
  • Bone Marrow / drug effects
  • Carbon Disulfide / metabolism
  • Cytochrome P-450 Enzyme System
  • Humans
  • Liver / drug effects
  • Lung / drug effects
  • Neoplasms, Experimental / chemically induced
  • Organothiophosphorus Compounds / metabolism
  • Organothiophosphorus Compounds / toxicity*
  • Oxygenases / antagonists & inhibitors
  • Parathion / metabolism
  • Phenobarbital / pharmacology
  • Thioacetamide / metabolism
  • Thiones / metabolism
  • Thiones / toxicity*

Substances

  • Antimetabolites
  • Organothiophosphorus Compounds
  • Thiones
  • Thioacetamide
  • Parathion
  • Cytochrome P-450 Enzyme System
  • Oxygenases
  • Carbon Disulfide
  • Phenobarbital