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The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification.
The PAR-domain basic leucine zipper (PAR bZip) transcription factors DBP, TEF, and HLF accumulate in a highly circadian manner in several peripheral tissues, including liver and kidney. Mice devoid of all three of these proteins are born at expected Mendelian ratios, but are epilepsy prone, age at an accelerated rate, and die prematurely. In the hope of identifying PAR bZip target genes whose altered expression might contribute to the high morbidity and mortality of PAR bZip triple knockout mice, we compared the liver and kidney transcriptomes of these animals to those of wild-type or heterozygous mutant mice. These experiments revealed that PAR bZip proteins control the expression of many enzymes and regulators involved in detoxification and drug metabolism, such as cytochrome P450 enzymes, carboxylesterases, and constitutive androstane receptor (CAR). Indeed, PAR bZip triple knockout mice are hypersensitive to xenobiotic compounds, and the deficiency in detoxification may contribute to their early aging.
Amino Acid Sequence, Animals, Aryl Hydrocarbon Hydroxylases/genetics, Basic-Leucine Zipper Transcription Factors/deficiency, Basic-Leucine Zipper Transcription Factors/genetics, Circadian Rhythm/physiology, Cytochrome P-450 Enzyme System/genetics, Cytochrome P-450 Enzyme System/metabolism, DNA-Binding Proteins/deficiency, DNA-Binding Proteins/genetics, Gene Expression Regulation, Enzymologic, Humans, Kidney/metabolism, Liver/metabolism, Mice, Mice, Knockout, Molecular Sequence Data, RNA, Messenger/genetics, RNA, Messenger/metabolism, Rats, Receptors, Cytoplasmic and Nuclear/genetics, Receptors, Cytoplasmic and Nuclear/metabolism, Steroid Hydroxylases/genetics, Transcription Factors/deficiency, Transcription Factors/genetics, Transcription, Genetic/genetics, Xenobiotics/metabolism
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