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J. Biol. Chem., Vol. 282, Issue 12, 8749-8758, March 23, 2007

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Nrf2-Keap1 Signaling Pathway Regulates Human UGT1A1 Expression in Vitro and in Transgenic UGT1 Mice^*

From the Laboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and of Pharmacology, University of California, San Diego, La Jolla, California 92093

The formation of -D-glucopyranosides (glucuronides) by the UDP-glucuronosyltransferases (UGTs) is a significant metabolic pathway that facilitates the elimination of small hydrophobic molecules such as drugs, dietary constituents, steroids, and bile acids. We elucidate here that an anti-oxidative response leads to induction of UGT1A1 through the Nrf2-Keap1 pathway. When human HepG2 cells were treated with the prooxidants tert-butylhydroquinone and -naphthoflavone, cellular UGT1A1 glucuronidation activities were increased. The induction of UGT1A1 proceeded following the overexpression of Nrf2 and was blocked following overexpression of Keap1, demonstrating that Keap1 suppresses Nrf2 activation of the UGT1A1 gene. Loss of function analysis for Nrf2 conducted by small interfering RNA revealed that induction of UGT1A1 was not seen in Nrf2 knock-out cells. To examine the contribution of oxidants toward the regulation of human UGT1A1 in vivo, transgenic mice bearing the human UGT1 locus (Tg-UGT1) were treated with tert-butylhydroquinone. Human UGT1A1 was markedly increased in small and large intestines as well as in liver. Gene mapping experiments including transfections of UGT1A1 reporter gene constructs into HepG2 cells coupled with functional analysis of Nrf2 expression and binding to anti-oxidant-response elements (ARE) resulted in identification of an ARE in the phenobarbital-response enhancer module region of the UGT1A1 gene. The ARE flanks the recently identified Ah receptor xenobiotic-responsive element. The results suggest that Nrf2-Keap1-dependent UGT1A1 induction by prooxidants might represent a key adaptive response to cellular oxidative stress that defends against a variety of environmental insults, including electrophile attacks and chemical carcinogenesis.

Received for publication, November 21, 2006 , and in revised form, January 26, 2007.

^* This work was supported in part by United States Public Health Service Grant GM49135 and ES10337. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of California, San Diego, Leichtag Biomedical Research Bldg., 9500 Gilman Dr., La Jolla, CA 92093-0722. Tel.: 858-822-0288; Fax: 858-822-0363; E-mail: rtukey{at}ucsd.edu.

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