Studies using structural analogs and inbred strain differences to support a role for quinone methide metabolites of butylated hydroxytoluene (BHT) in mouse lung tumor promotion

Toxicology. 2001 Mar 7;160(1-3):197-205. doi: 10.1016/s0300-483x(00)00449-2.

Abstract

Chronic treatment of BALB and GRS mice with BHT (2,6-di-tert-butyl-4-methylphenol) following a single urethane injection increases lung tumor multiplicity, but this does not occur in CXB4 mice. Previous data suggest that promotion requires the conversion of BHT to a tert-butyl-hydroxylated metabolite (BHTOH) in lung and the subsequent oxidation of this species to an electrophilic quinone methide. To obtain additional evidence for the importance of quinone methide formation, structural analogs that form less reactive quinone methides were tested and found to lack promoting activity in BHT-responsive mice. The possibility that promotion-unresponsive strains are unable to form BHTOH was tested by substituting this compound for BHT in the promotion protocol using CXB4 mice. No promotion occurred, and in-vitro work demonstrated that CXB4 mice are, in fact, capable of producing BHTOH and its quinone methide, albeit in smaller quantities. Incubations with BALB lung microsomes and radiolabeled substrates confirmed that more covalent binding to protein occurs with BHTOH than with BHT and, in addition, BHTOH quinone methide is considerably more toxic to mouse lung epithelial cells than BHT quinone methide. These data are consistent with the hypothesis that a two-step oxidation process, i.e. hydroxylation and quinone methide formation, is required for the promotion of mouse lung tumors by BHT.

Publication types

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

MeSH terms

  • Animals
  • Butylated Hydroxytoluene* / analogs & derivatives
  • Butylated Hydroxytoluene* / metabolism
  • Butylated Hydroxytoluene* / toxicity
  • Carcinogenicity Tests
  • Carcinogens / metabolism*
  • Disease Models, Animal
  • Female
  • Indolequinones*
  • Indoles / metabolism*
  • Lung / drug effects
  • Lung / metabolism
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microsomes / drug effects
  • Microsomes / metabolism
  • Quinones / metabolism*
  • Species Specificity
  • Structure-Activity Relationship
  • Urethane / toxicity

Substances

  • Carcinogens
  • Indolequinones
  • Indoles
  • Quinones
  • quinone methide
  • Butylated Hydroxytoluene
  • Urethane