PHARMACOLOGIC AND GENETIC-STUDIES ON THE MODULATORY EFFECTS OF BUTYLATED HYDROXYTOLUENE ON MOUSE LUNG ADENOMA FORMATION

  • 1 January 1984
    • journal article
    • research article
    • Vol. 73  (4) , 925-933
Abstract
Food additive butylated hydroxytoluene (BHT) (CAS: 128-37-0; 2,6-di-tert-butyl-p-cresol) can modulate the formation of lung adenomas in mice treated with the carcinogen urethan (CAS: 51-79-6; ethyl ester carbamic acid). An i.p. injection of BHT administered 6 h before a single urethan injection decreased the number of tumors formed, whereas 6 weekly BHT injections following a single urethan dose increased tumor multiplicity. Biotransformation of BHT was apparently required for both prophylaxis and enhancement. Pretreatment of mice with cedrene, which perturbs drug metabolism, prevented both of these BHT activities. Analogs of BHT with different substitutions at position 6 of the phenol ring also affected tumor formation. 2-t-Butyl-4-methylphenol inhibited, not enhanced, adenoma formation. 2-t-Butyl-4,6-dimethylphenol (BDMP) (CAS: 1879-09-0; 6-tert-butyl-2,4-xylenol); increased tumor number in A/J but not in the BALB/cByJ mouse strain; its prophylactic activity could not be measured since urethan injection following BDMP treatment was lethal. The presence of an alkyl group at this site on the phenol ring was not required for prophylaxis but was necessary for tumor enhancement. Different BHT metabolites apparently were responsible for each effect. Adenoma formation was enhanced by BHT in 4 strains of mice with a U+ phenotype (susceptible to urethan-induced lung adenomas); these strains were A, BALB/cBy, SWR/J, and RIIIS/J. BHT had no such effect in the U+ strain 129/J. A U+ B- phenotype (urethan inducible but unresponsive to BHT enhancement) also was found among the recombinant inbred lines originally derived from a cross between U+B+ BALB/cByJ and U-/B- C57BL/6ByJ progenitor strains. The genes determining sensitivity to urethan and to BHT apparently had recombined independently of each other. An inability to metabolize BHT was probably not involved in the B- phenotype, since BHT caused reversible lung damage in the 2 U+B- recombinant inbred lines and strain 129, and biotransformation was required for this effect. These U+B- mice can be used to characterize the lung toxic effects of BHT in the absence of its tumor-enhancing activity and will serve as valuable controls in studies on mechanisms of tumor enhancement.