The Effects of Human Recombinant Il-1β on Rat Hepatic and Renal Cytochrome P450-Mediated Monooxygenase Activities

Abstract

The effects of human recombinant IL-1β (BETALEUKIN) (6 × 10⁴ – 6 × 10⁶ U/Kg, intraperitoneally, single dose) on liver histology and cytochrome P450 (CYP450s)-mediated hepatic and renal monooxygenase activities were studied in adult male rats. rIL-1β (24 h after treatment) caused proinflammatory changes in liver histology in a dose-dependent manner which were the focal areas of hepatocellular dystrophy, perivascular polymorphonuclear cells infiltration, erythrocytes diapedesis, Kupffer cells and hepatocytes proliferation. Treatment with the rIL-1β caused the dose-dependent depression of the hepatic and renal CYP1A1/2-mediated ethoxyresorufin-O-deethylation (EROD), however showed variable effects of the CYP2E1-mediated p-nitrophenol hydroxylation (PNPH) and CYP3A-mediated erythromycin-N-demethylation (ERND). The hepatic PNPH activity was suppressed by the rIL-1β in doses of 6 × 10⁶ U/kg and 6 × 10⁴ U/Kg, and renal p-nitrophenol hydroxylation was suppressed only in a dose of 3 × 10⁵ U/Kg. The hepatic ERND activity was up regulated after the rIL-1β treatment (3 × 10⁵ U/Kg – 6 × 10⁵), and the renal ERND activity was suppressed in a dose of 3 × 10⁵ U/Kg. It is important that the possible effects of cytokines on individual CYP450s are characterized, so that concurrent drug therapy can be managed efficiently and pharmacokinetic interaction be avoided.