Eur. J. Biochem. 174,31-36 (1988) zyxwvuts 0 FEBS 1988 zyxwvutsrqp Potentiation and suppression of mouse liver cytochrome zyx P-450 isozymes during the acute-phase response induced by bacterial endotoxin Lesley A. STANLEY zyxwvutsrqp ', David J. ADAMS ', Robert LINDSAY I, Richard R. MEEHAN lS2, Warren LIAO and C. Roland WOLF I Imperial Cancer Research Fund Laboratory of Molecular Pharmacology and Drug Metabolism, Department of Biochemistry, Edinburgh Molecular Genetics Section, Medical Research Council Clinical and Population and Cytogenetics Unit, Western General Hospital, Edinburgh Department of Biochemistry and Molecular Biology, M.D. Anderson Hospital and Tumor Institute, Houston, Texas (Received October 27, 1987/January 12,1988) - EJB 87 1193 Infection and inflammation are known to affect the metabolism and disposition of drugs and carcinogens. We report a detailed study of the effects of bacterial endotoxin on the constitutive and inducible expression and activities of cytochrome P-450 isozymes from families P-4501, P-450IIB, P-45OIIC and P-450111. In general high doses of high endotoxin caused very marked suppression of P-450 isozymes and associated activities. However, this effect was differential, the expression of certain isozymes being only slightly reduced whereas others were suppressed to almost undetectable levels. Low doses of endotoxin also gave differential effects on cytochrome P-450 expression. Of particular interest was the very marked potentiation of the inductive effect of both 3-methylcholanthrene and phenobarbital. In the case of 3-methylcholanthrene the 10-fold induction of activity was increased to 24-fold by concomitant endotoxin administration. In this regard it was interesting that 3-methylcholanthrenewas an effective inducer of a wide variety of acute-phase proteins including metallothionein, serum amyloid A, fibrinogen and hemopexin. These data show that endotoxin, and therefore bacterial infection and inflammation, can have profound and differential effects on components of the cytochrome-P-450 monooxygenase system which could result in signifi- cant changes in susceptibility to the effects of drugs, chemical toxins and carcinogens. Two major systems that are central to protection from environmental insults are the cytochrome-P-450-dependent monooxygenase system and the acute-phase response associ- ated with tissue injury and infection. Both of these effects are mediated by genes expressed in the liver. The mammalian cytochrome-P-450-dependent mono- xygenase system is predominately located in the hepatic endo- plasmic reticulum and consists of a flavoprotein, NADPH - cytochrome-P-450 reductase, and a family of hemoprotein isozymes collectively termed cytochrome P-450. These catalyze the oxidative metabolism of endogenous substrates as well as of a large number of structurally diverse xenobiotics [I -31. This system is therefore important in defending the host against toxic foreign chemicals by helping to convert them to forms which can be more readily excreted. zyxwvu Correspondence to C. R. Wolf, Imperial Cancer Research Fund Laboratory of Molecular Pharmacology and Drug Metabolism, De- partment of Biochemistry, Hugh Robson Building, George Square, Edinburgh EH8 9XD, Scotland Abbreviations. PB, phenobarbital; MC, 3-methylcholanthrene. zyxwvuts Enzymes. NADPH -cytochrome-P-450 reductase (EC 1.6.2.4); cytochrome-P-450-dependent monooxygenase (EC 1.14.14.1). Note. According to the recently reported cytochrome P-450 no- menclature [49] PB1 is a member of family P-450IIC, PB2, family P-450111, PB3, family P-45011B, MC1. and MClb of family P-4.501. According to the nomenclature of Ryan et al. [50] PB3, = form b, MC1, = form d and MClb = form c. PB1 is equivalent to PB1 described by Waxman and Walsh zyxwvutsr [51]. PBzcappears to be part of the pregnenolone-I 6a-carbonitrile-inducible P-450 family as reported by Scheutz et al. [52] and Wrighton et al. [53]. Unfortunately, however, cytochrome P-450 can also convert relatively innocuous foreign compounds to toxic or carcinogeneic forms [3]. The importance of the cytochrome P-450s in xenobiotic metabolism is further underlined by the fact that many forms are induced following exposure of the host to foreign compounds [4]. Endotoxins are lipopolysaccharide components of the outer portion of the cell wall of gram-negative bacteria [5]. The systemic effects of endotoxins on homeostasis by invoking the host's acute-phase response to bacterial infection are well documented and include fever, plasma hypoglycaemia and immunomodulation [6 - 91. Hepatocytes respond to endo- toxin in a number of ways including a decrease in bile acid secretion, depletion of glycogen reserves and inhibition of both gluconeogenesis and oxygen consumption [lo]; stimu- lation of metallothionein synthesis [l 11 ; and the synthesis of large amounts of acute-phase reactants, notably serum amyloids A and P [12] and C-reactive protein [13]. The in- crease in synthesis of the above proteins during the acute- phase response is accompanied by a decrease in hepatic syn- thesis of other exported proteins including albumin [14- 161. Conflicting results have been reported regarding the behav- iour of non-exported proteins [17]. Previous reports have indi- cated that intraperitoneal doses of endotoxin cause a decrease in hepatic microsomal cytochrome-P-450-catalysed mono- oxygenase reactions [18 - 211. The cytochrome-P-450 mono- oxygenase system is complex and contains a wide variety of isozymes with different substrate specificities and differing mechanisms of regulation, and the above studies on the effects of endotoxin and interferons on P-450 activities have been