Abstract
Cytochromes P450 (P450s) are down-regulated in hepatocytes in response to inflammation and infection. This effect has been extensively studied in animal models, but significantly less is known about responses in humans and even less about responses in the absence of inducing agents. This article focuses on the effects of bacterial lipopolysaccaride (LPS), interleukin-6 (IL-6), tumor necrosis factor-α (TNF), interferon γ (IFN), transforming growth factor-β (TGF) and interleukin-1β (IL-1) on expression of CYP2B6 and the CYP2C mRNAs in human hepatocytes. These effects were compared with responses of the better studied and more abundant CYP3A4. CYP3A4 and CYP2C8 were down-regulated by all cytokine treatments. CYP2C18, which is expressed at very low levels in liver, was unaffected by cytokine treatments. The other CYP2Cs and CYP2B6 showed cytokine-specific effects. CYP2C9 and CYP2C19 showed almost identical response patterns, being down-regulated by IL-6 and TGF but not significantly affected by LPS, TNF, IFN, or IL-1. CYP2B6 mRNA responded only to IL-6 and IFN. IL-6 down-regulated the mRNAs of all P450s studied. Western blot analysis of P450 protein expression supported the mRNA data to a large extent, although some inconsistencies were observed. Our results show that human CYP2C8, 2C9, 2C18, 2C19, 2B6, and 3A4 responses to inflammation are independently regulated and indicate that this fine control may have a critical effect on human drug responses in disease states.
Footnotes
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This work was supported by Grants GM46897 and GM069971 from the National Institutes of Health (E.T.M.). Hepatocytes were provided by Dr. Steven Strom via the Liver Tissue Procurement and Distribution System, National Institutes of Health Contract N01-DK-9-2310.
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This work was presented in part at Experimental Biology 2006: Aitken AE and Morgan ET (2006) Regulation of human cytochrome P4502C mRNAs by cytokines. FASEB J20 (Suppl S):A425.4.
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doi:10.1124/dmd.107.015511.
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ABBREVIATIONS: P450, cytochrome P450; IL-6, interleukin-6; CAR, constitutive androstane receptor; PXR, pregnane X receptor; IFN, interferon γ; IL-1, interleukin-1β; TNF, tumor necrosis factor-α; TGF, transforming growth factor β; LPS, lipopolysaccaride; GAPDH, glyceraldehydes 3-phosphate dehydrogenase; PBS, phosphate buffered saline; RT, reverse transcriptase; PCR, polymerase chain reaction; NO, nitric oxide.
- Received March 2, 2007.
- Accepted June 15, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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Gene-Specific Effects of Inflammatory Cytokines on Cytochrome P450 2C, 2B6 and 3A4 mRNA Levels in Human Hepatocytes
