The effects of interleukin-6 (IL-6), the major inducer of the acute-phase reaction, on the expression of cytochrome P450IA1 (CYPIA1) were examined using human HepG2 hepatoma cells. Treatment of cells with IL-6 decreased the level of 3-methylcholanthrene-induced CYPIA1 protein and its mRNA. Nuclear runoff analysis revealed that the effect of IL-6 was largely transcriptional. IL-6 treatment of HepG2 cells increased mRNA for microsomal heme oxygenase, the rate-limiting enzyme in heme catabolism, suggesting that the suppressive effect of IL-6 on CYPIA1 mRNA may be due to a loss of heme. Consistent with this hypothesis, simultaneous treatment of cells with Sn-mesoporphyrin, an inhibitor of heme oxygenase, prevented the IL-6-mediated suppression of CYPIA1. These findings suggest that the suppression of P450IA1 mRNA by IL-6 appears to occur, at least in part, from the decline in free heme content as a result of the induction of heme oxygenase. Our results raise the possibility that other physiological as well as environmental stimuli which affect cellular heme concentrations may also modulate the expression of P450s.