SUPPRESSION OF CYTOCHROME P450-DEPENDENT AND UDP GLUCURONOSYL TRANSFERASE-DEPENDENT ENZYME-ACTIVITIES BY PROINFLAMMATORY CYTOKINES AND POSSIBLE ROLE OF NITRIC-OXIDE IN PRIMARY CULTURES OF PIG HEPATOCYTES
M. Monshouwer et al., SUPPRESSION OF CYTOCHROME P450-DEPENDENT AND UDP GLUCURONOSYL TRANSFERASE-DEPENDENT ENZYME-ACTIVITIES BY PROINFLAMMATORY CYTOKINES AND POSSIBLE ROLE OF NITRIC-OXIDE IN PRIMARY CULTURES OF PIG HEPATOCYTES, Toxicology and applied pharmacology, 137(2), 1996, pp. 237-244
Proinflammatory cytokines play an important role in the depression of
cytochrome P450 (CYP450)-dependent drug metabolism in mammals during i
nflammation and infection. Although much has been learned concerning t
he 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 pri
mary cultures of pig hepatocytes. A possible role of nitric oxide in c
ytokine-induced suppression of enzyme activities was studied by incuba
ting hepatocytes in the presence of N-G-nitro-L-arginine (L-NAME), a c
ompetitive inhibitor of nitric oxide (NO) biosynthesis. Incubation of
hepatocytes with interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6
), and tumor necrosis factor-alpha (TNF-alpha) decreased both oxidatio
n and glucuronidation activities dose dependently, in which the effect
s on glucuronidation activities were even more pronounced. IL-6 differ
ed from IL-1 alpha and TNF-alpha by inhibiting CYP450 and UDPGT more e
ffectively after 24 hr of incubation, whereas the inhibition by IL-1 a
lpha and TNF-alpha was more pronounced after 12 hr. Only at a concentr
ation of 500 U/ml did interferon-gamma (IFN-gamma) inhibit CYP450 and
UDPGT. The inhibition of CYP450 enzyme activities by cytokines was pro
bably 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 th
e decrease of glucuronidation by cytokines, as L-NAME slightly though
significantly prevented the inhibition of glucuronidation. (C) 1996 Ac
ademic Press, Inc.