Differential effect of cytokines on the phenobarbital or 3-methylcholanthrene induction of P450 mediated monooxygenase activity in cultured rat hepatocytes

doi:10.1016/0006-2952(94)00438-R

Biochemical Pharmacology

Volume 49, Issue 1, 6 January 1995, Pages 97-104

https://doi.org/10.1016/0006-2952(94)00438-R Get rights and content

Abstract

Cultured rat hepatocytes have been used to compare the relative activities of cytokines to inhibit the phenobarbital (PB) or 3-methylcholanthrene (MC) induction of cytochrome P4502B1 and 2B2 (P4502B1/2) or P4501A1 and 1A2 (P4501A1/2), respectively. Recombinant cytokines tested were human interleukin-6 (IL-6), interleukin-1α and -β (IL-1α and IL-1β, respectively), and rat γ-interferon (INFγ). Hepatocytes were cultured in the presence of 2mM PB or 1 μg MC/mL culture medium for 24 hr with or without the cytokines. Benzyloxyresorufin and ethoxyresorufin O-dealkylase (BROD and EROD, respectively) activities were determined as indices of P4502B1/2 and P4501A1/2, respectively. All cytokines produced a concentration-dependent inhibition of the PB induction of BROD activity. IL-1β and IL-6 were approximately equipotent with IC₅₀ values of 1–2 U/mL, causing greater than 90% inhibition of PB induction of BROD activity at a concentration of 50 U/mL culture medium. IL-1α tended to be less active. PB induction of BROD activity was also inhibited by INFγ, but higher concentrations (62.5 to 500 U/mL culture medium) were required. All cytokines were less effective in inhibiting the MC induction of EROD activity than the PB induction of BROD activity. IL-1β and IL-6, at 50 U/mL culture medium, inhibited EROD induction by only 35% compared with the greater than 90% inhibitory effect on the PB induction of BROD activity. INFγ was ineffective in inhibiting EROD activity at the concentrations studied. Western immunoblot analysis indicated that the cytokines prevented the ability of the inducers to increase the expression of P4502B1/2 and P4501A1/2 immunoreactive proteins, and this effect correlated with their inhibitory effect on induction of enzyme activity. The results suggest that inducible isoforms of cytochrome P450 differ in their susceptibility to regulation by the cytokines, and that cytokines possess differential activity to inhibit the induction of P450 isoforms, with IL-1β and IL-6 being the most effective.

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^†: Deceased, 7 April 1994.

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Research paperDifferential effect of cytokines on the phenobarbital or 3-methylcholanthrene induction of P450 mediated monooxygenase activity in cultured rat hepatocytes

Abstract

Lancet

Biochem Biophys Res Commun

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

Biochem Biophys Res Commun

J Biol Chem

Anal Biochem

Biochem Pharmacol

Biochem Biophys Res Commun

Fund Appl Toxicol

Arch Biochem Biophys

Biochem Biophys Res Commun

Pharmacokinetic and pharmacodynamic parameters affected by RE cell activators

Pharmacokinetics of immunomodulators

Altered theophylline kinetics

Lancet

Research paper
Differential effect of cytokines on the phenobarbital or 3-methylcholanthrene induction of P450 mediated monooxygenase activity in cultured rat hepatocytes