C57BL/6N mice were treated to induce tolerance, to modulate the mixed function oxidase system or to deplete glutathione (GSH) before injection with 400 mg 3-methylindole (3MI)/kg. Effect of pretreatment was determined by histologic comparison of pulmonary and nasal lesions 24 hours after 3MI. beta-Naphthoflavone and 3MI pretreatment significantly decreased 3MI-induced bronchiolar epithelial damage in male and female mice, while phenobarbital protection was significant only in female mice. Only beta-naphthoflavone decreased nasal olfactory epithelial damage. Pretreatment with piperonyl butoxide, SKF 525-A, or alpha-naphthoflavone had no significant effect on development of lesions. Diethylmaleate pretreatment significantly increased mortality and bronchiolar damage in both sexes. Significant differences between male and female mice were not detected in any group. The results suggest that pretreatment with low doses of 3MI or induction of cytochrome P-448 or P-450 protects against 3MI toxicosis while GSH depletion increases mortality and pulmonary lesions.