Xenobiotic metabolism in the fourth dimension: PARtners in time

Abstract

A significant portion of the transcriptome in mammals, including the PAR bZIP transcription factors DBP, HLF, and TEF, is under circadian clock control. In this issue of Cell Metabolism, Gachon and colleagues (Gachon et al., 2006) show that disruption of these three genes in mice alters gene expression patterns of many proteins involved in drug metabolism and in liver and kidney responses to xenobiotic agents. Triple mutant mice have severe physiological deficits, including increased hypersensitivity to xenobiotic agents and premature aging, highlighting the profound effect the circadian clock has on this important response system.

Figure 1. The circadian oscillator drives a cascade of temporally coordinated rhythmic gene expression that is necessary for a proper response to xenobiotics

The core circadian oscillator mechanism (top) is composed of two interlocking loops which produce rhythmic activity of the heterodimeric transcription factor composed of CLOCK (C) and BMAL1 (B). CLOCK and BMAL1 drive rhythmic gene expression of “output” genes, including those encoding the PAR-bZIP transcription factors DBP (D), HLF (H) and TEF(T). These transcription factors form homo- and heterodimers and activate other genes rhythmically, including those involved in the response to xenobiotics. These proteins drive expression of detoxification genes, including several Cytochrome P450s (CYPs), sulfotransferases (SULT), carboxylesterase (CES), and others (center box). In addition, these transcription factors also regulate genes encoding a retinoid receptor (CAR) that regulates detoxification genes in a xenobiotic-inducible manner (right box), and those encoding enzymes (ALAS1 and POR) involved in providing heme and electrons important for the activation of cytochrome P450s (right box). The net result of this cascade is the appropriately timed production of the many proteins needed for xenobiotic responsiveness as represented in the graph (bottom).