Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR (constitutive androstane receptor) and PXR (pregnane X receptor) in mouse liver during the acute phase response

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Abstract

Expression of P-450 (Cyp) enzymes is reduced in liver during the acute phase response, contributing to the decrease in bile acid levels and drug metabolism during infection. Nuclear hormone receptors CAR and PXR are key transactivators of Cyp2b and Cyp3a genes, respectively. Injection of bacterial lipopolysaccharide (LPS) induced the expected reduction in Cyp2b10 and Cyp3a mRNA levels in mouse liver. These decreases were associated with a marked reduction in CAR and PXR mRNA levels within 4 h following treatment. LPS-induced CAR and PXR repression were dose-dependent and sustained for at least 16 h. LPS treatment also reversed the up-regulation of Cyp3a in mice pre-treated with PXR ligand RU486. In addition, we observed a concomitant decrease in RXR (retinoid X receptor) mRNA levels, the obligatory partner of both CAR and PXR for high affinity binding to DNA. These findings represent one possible molecular mechanism underlying sepsis-induced repression of Cyp enzymes.

Section snippets

Materials and methods

Animals. Six-week-old female C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME) were maintained in a normal-light-cycle room and were provided with rodent chow and water ad libitum. Anesthesia was induced with halothane. To determine the effect of the APR on CAR and PXR mRNA levels, mice were injected intraperitoneally (IP) with 0.1–100μg of LPS (Escherichia coli 55:B5, Difco Laboratories, Detroit, MI) in saline or with saline alone. In all other experiments, mice were injected IP with 100μg of

Results and discussion

The decreased metabolism of drugs in humans during infection is well documented [27]. Consistent with these data, our mouse model of LPS-induced acute inflammation resulted in the expected decrease in the expression of two classes of Cyp enzymes involved in drug metabolism [10]. As shown in Fig. 1, we observed an 80% decrease (p<0.01) in Cyp2b10 mRNA levels as soon as 4 h after LPS administration. This effect on Cyp2b10 expression was sustained for at least 16 h with LPS treatment inducing a

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    This work was supported by grants from the Research Service of the Department of Veterans Affairs and by National Institutes of Health grants DK 49448 and AR 39639.

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