Hepatic P450 activities are profoundly affected by various infectious and inflammatory stimuli, and this has clinical and toxicological consequences. Whereas the expression of most P450s in the liver is suppressed, some are induced. Many of the effects observed in vivo can be mimicked by pro-inflammatory cytokines and IFNs, and P450s are differentially regulated by these agents. Therefore, different cytokine profiles and concentrations in the vicinity of the hepatocyte in different models of inflammation may result in qualitatively and quantitatively different effects on populations of P450s. In addition to cytokines, glucocorticoids may have an important role in P450 regulation in stress conditions, including that caused by inflammatory stimuli. Although in many cases the decreases in activity are due primarily to a down-regulation of P450 gene transcription, it is likely that modulation of RNA and protein turnover, as well as enzyme inhibition, contributes to some of the observed effects. The mechanisms whereby these effects are produced may also vary with both the P450 under study and the time course of the effect. The complexity of the P450 response to inflammation and infection means that all of the above factors must be considered when trying to predict the effect of a given infectious or inflammatory condition on the clinical or toxic response of humans or animals to an administered drug or toxin. The question of whether the down-regulation of the hepatic P450 system to inflammation or infection is a homeostatic or pathological response cannot be answered at present. It is difficult to discern the physiological benefit of reducing hepatic P450 activities, unless it is to prevent the generation of reactive oxygen species generated by uncoupled catalytic turnover of the enzymes. On the other hand, as we proposed some years ago [64], the suppression of P450 may be due to the liver's need to utilize its transcriptional machinery and energy for the synthesis of APPs involved in the inflammatory response. In that case, one could ask why the organism has gone to the trouble of employing differential mechanisms for suppression of P450. One answer could be that the response evolved after the divergence of many of the P450 genes, necessitating the evolution of multiple redundant mechanisms for P450 suppression. In contrast to the down-regulation of P450s in the liver, the induction of several forms in this and other tissues suggests a more specific homeostatic role of these effects, e.g., in generation or catabolism of bioactive metabolites.

Regulation of Cytochromes P450 During Inflammation and Infection

Human cytochromes P450

Since their initial description in 1957, the interferons (IFNs) have been increasingly used to treat a wide array of diseases. Acute adverse effects, i.e. ‘flu-like’ syndromes, hypo- or hypertension, tachycardia, headache, myalgias and gastrointestinal disorders, occur within the first hour or day after starting treatment. They are seldom treatment-limiting and are easily manageable.

Clinical toxicity of the interferons.

Molecular Cloning, Expression, and Functional Significance of a Cytochrome P450 Highly Expressed in Rat Heart Myocytes

Alteration of drug biotransformation and elimination during infection and inflammation.

The aim of this study was to clarify the mechanism by which cytochrome P450 (P450)-mediated catalytic activity is decreased following interferon (IFN) administration. Microsomal steroid hydroxylation was assessed to test the hypothesis that IFN selectively decreases the activities of individual P450 isozymes in male rats. Thus, recombinant rat IFN gamma (r-rat IFN gamma) treatment produced 40% and 17% reductions in androst-4-ene-3,17-dione (androstenedione) 6 beta- and 16 beta-hydroxylation, respectively. Androstenedione 16 alpha- and 7 alpha-hydroxylation were unaltered following r-rat IFN gamma treatment. Similar changes in the androstenedione hydroxylation pathways were observed following administration of naturally derived rat IFN alpha/beta. Microsomal levels of P450IIIA2, the male-specific constitutive steroid 6 beta-hydroxylase, were lower after administration of r-rat IFN gamma (42% of control fractions). Furthermore, hepatic P450IIIA2 mRNA was found to be decreased to a similar extent by r-rat IFN gamma. These findings suggest that IFN selectively decreases the content of this isozyme by a mechanism involving altered mRNA regulation. Sex steroids were unlikely to have mediated the decrease in P450IIIA2 levels since serum estradiol and testosterone levels were unchanged by r-rat IFN gamma. In order to determine whether IFN alters the expression of P450IIIA1, a steroid-inducible member of the P450IIIA gene subfamily which is not expressed in untreated rat liver, adult female rats (which lack P450IIIA2) were coadministered pregnenolone 16 alpha-carbonitrile and r-rat IFN gamma. However, IFN failed to impair the induction of androstenedione 6 beta-hydroxylation produced by pregnenolone 16 alpha-carbonitrile. These findings suggest that although IFN decreases the expression of P450IIIA2, it may not down regulate the expression of other steroid-inducible P450IIIA proteins. In view of the existence of human P450IIIA orthologs which catalyze the metabolism of several important therapeutic agents, the findings of this study may help predict possible drug interactions in patients receiving IFN.

Interferon down regulates the male-specific cytochrome P450IIIA2 in rat liver.

Elevated serum estradiol concentrations and specific changes in the biliary excretion of some androstenedione metabolites have been reported in male rats with portal bypass produced by portal vein ligation (PVL). In this study, the hypothesis that male-specific forms of cytochrome P-450 are altered after PVL was tested by measuring microsomal steroid hydroxylase activities. Consistent with earlier findings in the intact animal, androstenedione 16 alpha-hydroxylase activity was reduced after PVL to 44% of control (P less than 0.05). Other pathways of androstenedione hydroxylation, and total estrogen formation (after androstenedione aromatization) were unchanged. Although total estrogen formation was not different, a sevenfold greater proportion of estradiol was produced in PVL rat microsomes. Additional experiments revealed that PVL selectively reduced the rate of microsomal estradiol 16 alpha-hydroxylation (to 56% of control, P less than 0.02). Levels of cytochrome P-450UT-A, the microsomal steroid 16 alpha-hydroxylase, were lower after PVL (56% of control, P less than 0.05), so that the present observations are consistent with the earlier suggestion that portal bypass is associated with the selective downregulation of this enzyme. Since downregulation of cytochrome P-450UT-A also occurs in experimental hepatic cirrhosis, portal hypertension may well contribute significantly to altered drug metabolism in liver disease. Impaired hepatic elimination of androstenedione by hydroxylation may indirectly enhance extrahepatic aromatization of the androgen. The decreased activity of hepatic estradiol 16 alpha-hydroxylation after PVL would enhance the accumulation of estradiol, the biologically more potent estrogen.

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Downregulation of the male-specific hepatic microsomal steroid 16 alpha-hydroxylase, cytochrome P-450UT-A, in rats with portal bypass. Relevance to estradiol accumulation and impaired drug metabolism in hepatic cirrhosis.

The microsomal content and activity of the principal male-specific cytochrome P450 2C11 are reduced in cirrhotic rat liver. In order to define the pathophysiological mechanism for such changes, the present study was undertaken to determine the time course of impaired P450 2C11 expression in relation to the development of cirrhosis during intake of a choline-deficient diet. Fatty infiltration of the liver was evident after 6 weeks of intake but hepatic fibrosis was not present until 10 weeks, when fine fibrotic bands in a perisinusoidal distribution were observed. Fibrotic bands were progressively more prominent at 20 and 25 weeks and cirrhosis was established by 30 weeks of dietary intake. Portal pressure, as measured by saline manometry and indicated by splenomegaly, appeared to increase gradually after 6 weeks and by 25 weeks values were significantly greater than controls. The microsomal content of P450 2C11 and its associated steroid 16 alpha-hydroxylase activity were unchanged at 6 weeks but were decreased to around 30% of control from 10 weeks of intake of the choline-deficient diet to the end of the experimental period (30 weeks). Serum bile acids were approximately 2-fold greater in choline-deficient rats from 10 weeks. Similarly, serum estradiol concentrations were elevated (to 2.5-fold of control) in male rats after 10 weeks intake of the choline-deficient diet; this increase was sustained in 30-week cirrhotic rats. On the other hand, there was no evidence of altered serum testosterone until 30 weeks of dietary deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

I Mehta

Papers

Interferon down regulates the male-specific cytochrome P450IIIA2 in rat liver.

Downregulation of the male-specific hepatic microsomal steroid 16 alpha-hydroxylase, cytochrome P-450UT-A, in rats with portal bypass. Relevance to estradiol accumulation and impaired drug metabolism in hepatic cirrhosis.

Impaired expression of microsomal cytochrome P450 2C11 in choline-deficient rat liver during the development of cirrhosis.

Interferon down-reguiates the steroid 6B-hydroxylase, cytochrome P-450 PCN-E