Biochemical and Biophysical Research Communications
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☆
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– 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 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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2022, Drug Metabolism and PharmacokineticsCitation Excerpt :The P450s family of drug-metabolizing enzymes are known to alter their expression levels during inflammation [6]. Cytokines such as interleukins and TNF-α activate NF-κB, which regulates transcription factors for P450s, for example, the aryl hydrocarbon receptor [7,8], constitutive androstane receptor [9–11] and pregnane X receptor [9,10,12]. Furthermore, NF-κB directly regulates the expression of P450s, such as CYP1A1, CYP2B1/2, CYP2C11, CYP2D5, CYP2E1, CYP3A7 and CYP27B by binding to their promoter regions [13].
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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.