Male Sprague-Dawley rats were treated intraperitoneally with corn oil, the aryl hydrocarbon receptor (AHR) agonist b-naphthoflavone (bNF), or the relatively weak AHR agonist ␣-naphthoflavone (␣NF). Animals treated with bNF experienced a significant loss (12%) of total body mass over 5 days and a dramatic elevation of CYP1A1 mRNA in all of the organs studied. Treatment with ␣NF had no significant effect on body mass after 5 days and caused only minor increases of liver, kidney, and heart CYP1A1 mRNA. In contrast, lung CYP1A1 mRNA was increased by ␣NF treatment to levels comparable to that seen with bNF treatment. CYP2E1 mRNA levels were also elevated in liver, lung, kidney, and heart in response to bNF treatment, whereas ␣NF was without effect. Large increases of CYP1A1-dependent 7-ethoxyresorufin O-deethylation (EROD) activity occurred with microsomes prepared from the tissues of bNF-treated animals. Comparatively small changes were associated with ␣NF treatment, with the exception of lung, where EROD activity was increased to approximately 60% of that with bNF treatment. CYP2E1-dependent p-nitrophenol hydroxylase (PNP) activity was also increased by bNF treatment in microsomes prepared from kidney (3.1fold), whereas ␣NF was without effect. In contrast, ␣NF or bNF treatment caused significant decreases of lung microsomal PNP (72% and 27% of corn oil control, respectively) and 7-pentoxyresorufin O-deethylation (48% and 17% of corn oil control, respectively) activities, indicating that PNP activity may be catalyzed by P450 isoforms other than CYP2E1 in rat lung. We conclude that bNF and ␣NF have differential effects on the expression and catalytic activity of CYP1A1 and CYP2E1, depending upon the organ studied. These changes most likely occur as a result of the direct actions of these compounds as AHR agonists, in addition