Arsenite decreases CYP3A4 and RXRalpha in primary human hepatocytes.

Article Details

Citation

Copy to clipboard

Noreault TL, Kostrubsky VE, Wood SG, Nichols RC, Strom SC, Trask HW, Wrighton SA, Evans RM, Jacobs JM, Sinclair PR, Sinclair JF

Arsenite decreases CYP3A4 and RXRalpha in primary human hepatocytes.

Drug Metab Dispos. 2005 Jul;33(7):993-1003. Epub 2005 Apr 15.

PubMed ID

15833926 [ View in PubMed

]

Abstract

Arsenic is a naturally occurring, worldwide contaminant implicated in numerous pathological conditions in humans, including cancer and several forms of liver disease. One of the contributing factors to these disorders may be the alteration of cytochrome P450 (P450) levels by arsenic. P450s are involved in the oxidative metabolism and elimination of numerous toxic chemicals. CYP3A4, a major P450 in humans, is involved in the metabolism of half of all currently used drugs. Acute exposure to arsenite decreases the induction of CYP1A1/2 proteins and activities in cultured human hepatocytes, as well as CYP3A23 in cultured rat hepatocytes. Here, in primary cultures of human hepatocytes, we assessed the effects of acute arsenite exposure on CYP3A4 and several transcription factors involved in CYP3A4 expression. The concentrations of arsenite used in these studies were nontoxic to the hepatocytes and failed to elicit an oxidative response. Treatment with arsenite in the presence of CYP3A4 inducers, rifampicin (Rif) or phenobarbital, caused major decreases in CYP3A4 mRNA, protein, and activity. In addition, the levels of CYP3A4 in untreated cells were decreased following arsenite treatment. Transcription of the CYP3A4 gene is primarily regulated by heterodimers of the retinoid X receptor alpha (RXRalpha) and the pregnane X receptor (PXR). We found that arsenite failed to affect expression of PXR or the transcription factor Sp1, yet caused a significant decrease in PXR responsiveness to Rif. Arsenite caused a large decrease in nuclear RXRalpha protein and, to a lesser extent, RXRalpha mRNA. These results suggest that arsenite inhibits both untreated and induced CYP3A4 transcription in primary human hepatocytes by decreasing the activity of PXR, as well as expression of the nuclear receptor RXRalpha.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Arsenic trioxide	Cytochrome P450 3A4	Protein	Humans	Unknown	Inhibitor	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Phenobarbital	Approved Investigational	CYP3A4	1576	upregulated	Phenobarbital results in increased expression of CYP3A4 mRNA	7q22.1
Rifampicin	Approved	CYP3A4	1576	upregulated	Rifampin results in increased expression of CYP3A4 mRNA	7q22.1