Genomic characterization and regulation of CYP3a13: role of xenobiotics and nuclear receptors.
We report that CYP3a13 gene, located on mouse chromosome 5, spans 27.5 Kb and contains 13 exons. The transcription start site is 35 bp upstream of the coding region and results in a 109 bp 5' untranslated region. CYP3a13 promoter shows putative binding sites for retinoid X receptor, pregnane X receptor, and estrogen receptor. CYP3a13 shows a broad tissue distribution with predominant expression in liver. Although CYP3a13 shares 92% nucleotide identity with the female-specific rat CYP3A9, its expression does not exhibit sexual dimorphism. Ligand activation of peroxisomal proliferator-activated receptor-gamma and retinoid X receptor inhibit expression of CYP3a13 at the transcription level in a tissue-specific manner. Another novel finding is hepatic induction of CYP3a13 by dexamethasone occurring only in pregnane X receptor null mice. We also report that pregnane X receptor is essential to maintain robust in vivo basal levels of CYP3a13 in contrast to CYP3a11. CYP3a13 protein expressed in vitro can metabolize clinically active drugs ethylmorphine and erythromycin, as well as benzphetamine. We conclude that CYP3a13 is regulated differentially by various nuclear receptors. In humans this may lead to altered drug metabolism, as many of the newly synthesized ligands/drugs targeted toward these nuclear receptors could influence CYP3A gene expression.
Anakk
Sayeepriyadarshini
S
Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston 77225, USA.
Kalsotra
Auinash
A
Shen
Qi
Q
Vu
Mary T
MT
Staudinger
Jeffrey L
JL
Davies
Peter J A
PJ
Strobel
Henry W
HW
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D040461:Gene Components; D005786:Gene Expression Regulation; D023281:Genomics; D008024:Ligands; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D012727:Sex Characteristics; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism*
D008024:Ligands; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D015262:Xenobiotics; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; C496508:Cyp3a11 protein, mouse; C496509:Cyp3a13 protein, mouse; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating