Interferon down-regulates expression of cytochrome P-450 3A in male rats. This study explored the hypothesis that interferon therefore decreases the metabolism of drugs catalyzed by cytochrome P-450 3A. Initial experiments in male rats used microsomal erythromycin N-demethylase activity as a probe for cytochrome P-450 3A catalytic activity. After administration of rat interferon-gamma, erythromycin metabolism was impaired (53% of control; p < 0.01). This change correlated with the decline in cytochrome P-450 3A-dependent androstenedione 6 beta-hydroxylase activity, indicating that the decrease in erythromycin N-demethylase activity could be attributed to interferon-mediated suppression of cytochrome P-450 3A. We then used the [14C]N-methyl erythromycin breath test to assess the activity of hepatic cytochrome P-450 3A in rats and human subjects before and after a single dose of interferon. In rats, rat interferon-gamma decreased erythromycin metabolism to 57% of control (p < 0.005). In the human study, six patients with chronic active hepatitis C and four healthy controls were examined 20 to 26 hr after receiving a subcutaneous injection of human interferon-alpha 2b. Interferon produced a small decrease (median = 15%; range = 3% to 35%) in erythromycin metabolism (p < 0.05), as determined by 2-hr excretion of 14CO2 in the breath. Thus interferon-mediated suppression of cytochrome P-450 3A is less strong in human subjects than in male rats.(ABSTRACT TRUNCATED AT 250 WORDS)