Investigation of the CYP2C9 Induction Profile in Human Hepatocytes by Combining Experimental and Modelling Approaches

Abstract

The goal of the present review is to characterise the induction profile of CYP2C9, a member of the cytochrome P450 superfamily. Since the mechanism of CYP2C9 induction is fairly complex, with parallel processes triggered by various inducers, an evaluation of the experimental results is often a great challenge. At least three nuclear receptors, the glucocrticoid receptor (GR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), are known to mediate the CYP2C9 gene induction in man. However, mathematical modelling and simulation can provide an appropriate tool for the interpretation of CYP2C9 regulatory mechanisms. As an example, we present modelling and simulation approaches of the CYP2C9 gene expression in human hepatocytes treated with well-known CYP2C9 inducers: the steroid hormone precursor dehydroepiandrosterone (DHEA) and the synthetic glucocorticoid dexamethasone (DXM). The results of the analysis suggest that in addition to the potent function of GR and the further involvement of PXR and CAR activated by DXM or DHEA, an additional factor might play a role in CYP2C9 regulation by DHEA. The novel potential candidate for DHEA action in CYP2C9 induction is likely to be the estrogen receptor. Additionally, the balance of DHEA sulphation-desulphation processes should also be considered in any description of DHEA-induced CYP2C9 profiles.

Association of CYP2C9*2 With Bosentan-Induced Liver Injury

“…This SNP is located in a transcription factor binding region and DNaseI hypersensitivity cluster as confirmed by ChiP-Seq and DNase-Seq data from ENCODE and has been associated in a genome wide association study with dehydroepiandrosterone sulfate levels. There is no evidence that CYP2C9 is directly involved in dehydroepiandrosterone or dehydroepiandrosterone sulfate metabolism, however dehydroepiandrosterone is a known CYP2C9 inducer (39). CYP2C9*2 is also in linkage disequilibrium (R 2 = 0.462) with an intronic SNP (rs4086116), which has been associated with warfarin (40) and acenocumarol dosing (41).…”

Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping

“…Anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) antibody (clone 6C5, MAB374) was purchased from Millipore (Temecula, CA). Rabbit polyclonal antibodies against c-Jun (sc-44), JunD (329;, c-Fos (sc-52), Nrf2 (C-20; sc-722), Activating transcription factor 2 (ATF2) (C-19; sc-187), and ATF4 (C-20; sc-200) Bayliss and Skett (1996), as previously described (Belic et al, 2009). Hepatocytes having viability better than 90% as determined by trypan blue exclusion were used in the experiments.…”

Effects of Methoxychlor and 2,2-bis (<b><i>p</i></b>-Hydroxyphenyl)-1,1,1-Trichloroethane on Cytochrome P450 Enzyme Activities in Human and Rat Livers

“…These enzymes play a critical role in the metabolism of a variety of endogenous and exogenous compounds, including steroids, drugs, and environmental pollutants [3,25]. Diclofenac, omeprazole, dextromethorphan, and midazolam were used as the common substrates of human CYP2C9 and rat CYP2C11, human CYP2C19 and rat CYP2C6, human CYP2D6 and CYP2D2, and human CYP3A4 and CYP3A1, respectively.…”

“…They are involved in the metabolism of endogenous and exogenous compounds, including steroids, fatty acids, bile acids, lipid-soluble vitamins, drugs, and environmental pollutants [1,2,3]. Most CYPs are expressed in the liver, but some are localized in extrahepatic tissues.…”