Suppression of Cytochrome P450- and UDP Glucuronosyl Transferase-Dependent Enzyme Activities by Proinflammatory Cytokines and Possible Role of Nitric Oxide in Primary Cultures of Pig Hepatocytes

doi:10.1006/taap.1996.0077

Toxicology and Applied Pharmacology

Volume 137, Issue 2, April 1996, Pages 237-244

https://doi.org/10.1006/taap.1996.0077 Get rights and content

Abstract

Proinflammatory cytokines play an important role in the depression of cytochrome P450 (CYP450)-dependent drug metabolism in mammals during inflammation and infection. Although much has been learned concerning the effects and mechanisms of cytokine-mediated suppression of CYP450, there is limited knowledge about how cytokines affect UDP glucuronosyl transferases (UDPGT). The aim of the present study was to investigate the effects and dose dependency of recombinant human proinflammatory cytokines on both CYP450- and UDPGT-dependent enzyme activities in primary cultures of pig hepatocytes. A possible role of nitric oxide in cytokine-induced suppression of enzyme activities was studied by incubating hepatocytes in the presence ofN^G-nitro-L-arginine (L-NAME), a competitive inhibitor of nitric oxide (NO) biosynthesis. Incubation of hepatocytes with interleukin-1α (IL-1α), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) decreased both oxidation and glucuronidation activities dose dependently, in which the effects on glucuronidation activities were even more pronounced. IL-6 differed from IL-1α and TNF-α by inhibiting CYP450 and UDPGT more effectively after 24 hr of incubation, whereas the inhibition by IL-1α and TNF-α was more pronounced after 12 hr. Only at a concentration of 500 U/ml did interferon-γ (IFN-γ) inhibit CYP450 and UDPGT. The inhibition of CYP450 enzyme activities by cytokines was probably not due to the production of NO, because L-NAME totally blocked NO production but had no effect on the cytokine-induced suppression of CYP450 enzyme activities. However, there might be a role for NO in the decrease of glucuronidation by cytokines, as L-NAME slightly though significantly prevented the inhibition of glucuronidation.

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Regular ArticleSuppression of Cytochrome P450- and UDP Glucuronosyl Transferase-Dependent Enzyme Activities by Proinflammatory Cytokines and Possible Role of Nitric Oxide in Primary Cultures of Pig Hepatocytes

Abstract

Regular Article
Suppression of Cytochrome P450- and UDP Glucuronosyl Transferase-Dependent Enzyme Activities by Proinflammatory Cytokines and Possible Role of Nitric Oxide in Primary Cultures of Pig Hepatocytes