Lithocholic acid decreases expression of UGT2B7 in Caco-2 cells: a potential role for a negative farnesoid X receptor response element.

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Lu Y, Heydel JM, Li X, Bratton S, Lindblom T, Radominska-Pandya A

Lithocholic acid decreases expression of UGT2B7 in Caco-2 cells: a potential role for a negative farnesoid X receptor response element.

Drug Metab Dispos. 2005 Jul;33(7):937-46. Epub 2005 Apr 8.

PubMed ID

15821044 [ View in PubMed

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Abstract

Human UDP-glucuronosyltransferase (UGT) 2B7 is the major isoform catalyzing the glucuronidation of a variety of endogenous compounds including bile acids. To determine the role of bile acids in the regulation of UGT2B7 expression, Caco-2 cells were incubated with the natural human farnesoid X receptor (hFXR) ligand, chenodeoxycholic acid, as well as the secondary bile acid, lithocholic acid, derived from chenodeoxycholic acid. Incubation of Caco-2 cells with lithocholic acid in the absence of exogenous hFXR resulted in a dose-dependent down-regulation of UGT2B7 mRNA levels, with an IC(50) of 13 microM. Similar down-regulation was also observed with chenodeoxycholic acid; however, much higher concentrations were required. Transient transfection of Caco-2 cells with hFXR suppressed UGT2B7 mRNA expression both in the absence and presence of ligand. UGT2B7 promoter transfection experiments and deletion/mutation analysis showed that lithocholic acid-activated hFXR decreased UGT2B7 promoter activity via a negative hFXR response element (NFRE) located between nucleotides -148 and -134. Cotransfection with hFXR and/or human retinoid X receptor further enhanced the repression. Electrophoretic mobility shift assays additionally confirmed the role of NFRE in UGT2B7 down-regulation by lithocholic acid. These findings suggest that lithocholic acid, an activator of nuclear hFXR, acts as a negative regulator of UGT2B7 expression, indicating that hFXR may play an essential role in lithocholic acid homeostasis through negative regulation of this UGT that is involved in lithocholic acid biotransformation. Therefore, it is postulated that lithocholic acid toxicity may be due to down-regulation of genes involved in its detoxification, including UGT2B7, leading to limited excretion of lithocholic acid from the body.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Chenodeoxycholic acid	UDP-glucuronosyltransferase 2B7	Protein	Humans	Unknown	Inhibitor	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Chenodeoxycholic acid	Approved	FABP6	2172	upregulated	Chenodeoxycholic Acid results in increased expression of FABP6 mRNA	5q33.3
Chenodeoxycholic acid	Approved	UGT2B7	7364	downregulated	Chenodeoxycholic Acid results in decreased expression of UGT2B7 mRNA	4q13.2