Effects of interleukin 1ß (IL-1ß) and IL-1ß/interleukin 6 (IL-6) combinations on drug metabolizing enzymes in human hepatocyte culture.

Exposure to cytokines can down-regulate hepatic cytochrome P450 enzymes. Accordingly, relief of inflammation by cytokinetargeted drug therapy has the potential to up-regulate cytochrome P450s and thereby increase clearance of co-administered drugs. This study examined the effects of the inflammatory cytokine, interleukin 1ß (IL-1ß), and IL-1ß/interleukin 6 (IL-6) combinations on drug metabolizing enzymes in human hepatocyte culture. Treatment of hepatocytes with IL-1ß revealed suppression of mRNA expression of several clinically important cytochrome P450 isoenzymes, with EC50 values that differed by isoenzyme. Suppression of CYP1A2 activity by IL-1ß could not be measured in 3 of 5 donors due to lack of response, and in the two remaining donors the average EC50 was 450 pg/mL. CYP3A activity had an EC50 of suppression of 416 ± 454 pg/mL. Measurable EC50s were obtained for all 5 donors for CYP2C8, 3A4, 3A5, 4A11 and IL-6R mRNA with fold differences which varied between 9.5-fold (CYP2C8) to 109-fold (CYP4A11). When hepatocytes were treated with IL-1ß and IL-6 in combination at concentrations which ranged from 1-100 pg/mL, IL-6 was the main determinant of increases in acute phase response marker mRNA and of decreases in CYP3A4 mRNA. There was no synergy between IL-1ß and IL-6 in the regulation of cytochrome P450 mRNA when dosed in combination, although the effects of the two cytokines in combination were additive in certain instances. These data indicate that IL-1ß and IL-6 both suppress cytochrome P450 mRNA and enzyme levels in vitro and that, at similar physiologically-relevant concentrations in vitro, IL-6 is more potent than IL-1ß.