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Steroid and xenobiotic receptor (SXR), cytochrome P450 3A4 and multidrug resistance gene 1 in human adult and fetal tissues

2005; Elsevier BV; Volume: 231; Issue: 1-2 Linguagem: Inglês

10.1016/j.mce.2004.12.005

1872-8057

Yasuhiro Miki, Takashi Suzuki, Chika Tazawa, Bruce Blumberg, Hironobu Sasano,

Pharmacological Effects and Toxicity Studies

The steroid and xenobiotic receptor (SXR) has been demonstrated to play an important role in the regulation of the cytochrome P450 3A4 gene (CYP3A4) and multidrug resistance gene 1 (MDR1) by both endogenous and xenobiotic substrates. SXR and its rodent ortholog PXR exhibit marked differences in their ability to be activated by xenobiotic inducers. This suggests that results obtained by rodent models may not always accurately predict responses to the same compounds in humans. SXR expression was demonstrated in the human liver and intestine, but its systemic distribution remains unknown. Therefore in this study, we first characterized the expression of SXR and its target genes CYP3A4, and MDR1 in human adult and fetal tissues using quantitative RT-PCR, immunoblotting, and combined laser capture microscopy and RT-PCR analysis. SXR mRNA and protein are expressed in adult and fetal liver, lung, kidney, and intestine. There is a close association between the expression of SXR and its target genes in all of the tissues examined. The amounts of SXR mRNA in the liver and intestine reached maximal levels in young adults (15-38 years old) and then subsequently decreased to less than half of the maximal levels with aging. These findings demonstrated age-related differences in the body's capacity to metabolize steroids and xenobiotic compounds and suggest an important role for SXR and its target genes, CYP3A4 and MDR1 in this process.