Coordinate regulation of human drug-metabolizing enzymes, and conjugate transporters by the Ah receptor, pregnane X receptor and constitutive androstane receptor
Introduction
It is increasingly recognized that cascades of Phase I and II enzymes and transporters act together to protect the body against the accumulation of potentially harmful lipid-soluble compounds. In addition to polymorphisms in the coding region, interindividual levels and activities of the involved proteins are largely determined by complex transcriptional control including actions of xenosensors such as the Ah receptor (AHR) [1], [2], CAR (NR1I3) and PXR (NR1I2) [2], [3], [4], [5], [6], [7]. Notably, these nuclear receptors act as multifunctional switches; for example, the AHR is involved in organ development in addition to adaptive regulation of detoxification. Previously, coordinate regulation of Phase I and II enzymes by AHR and Nrf2 has been discussed, the latter transcription factor controlling a gene battery involved in protection against oxidative stress [8]. However, due to extensive cross-talk between AHR, CAR and PXR, it seemed desirable to discuss their regulation and impact on drug metabolism and transport together; for example, the AHR appears to be a target gene of PXR [4], and CAR may be regulated by the AHR [9]. They belong to different gene superfamilies; the AHR is a member of the basic helix–loop–helix PAS (Per-Arnt-Sim) family [1] whereas PXR and CAR are type 2 members of the steroid receptor family characterized by heterodimerization with the common partner RXR (NR2B1/2/3) [7]. CAR/PXR and the AHR are the key mediators of the classic phenobarbital- and 3-methylcholanthrene-type induction of microsomal drug metabolism, respectively [10], [11], [12]. The genetic basis for coordinate expression of enzymes and transporters is represented in part by common DNA binding motifs present in the regulatory region of target genes. Evolution of common binding motifs hints to considerable functional advantages for the mammalian organism by coordinate regulation of Phase I and II metabolism and transport. It is noteworthy that – in addition to up- and downregulation of target genes – these receptors also regulate basal expression of proteins [13]. Furthermore, the receptors are again under the hierarchical control of regulators [14].
Accumulating evidence suggests considerable species differences in the regulation of biotransformation between rodents and humans. Therefore, the present commentary focuses on human drug metabolism and transport. Hepatic and intestinal CYPs and UGTs as major Phase I and II enzymes together with conjugate uptake and efflux transporters are emphasized to eventually be able to compare regulatory mechanisms with pharmacokinetic data on the bioavailability of drugs and their enterohepatic circulation. Phase II metabolism necessitates transport of the resulting polar conjugates out of cells. These export transporters have been subsummized as Phase III. Conjugates can also be taken up into cells, for example, into hepatoctes for biliary excretion; these uptake processes have been termed Phase 0.
Interestingly, xenobiotic metabolizing enzymes, conjugate transporters as well as their xenosensors are also involved in biotransformation of endobiotics including bile acids, bilirubin, and thyroxin [2], [5], [6], [15]. Expectedly, transcriptional regulatory coupling between these enzymes and transporters is tight in homeostatic control of endobiotics. Conceivably, coupling was also shaped by detoxification of dietary phytochemicals and ubiquitous contaminants to which organisms were exposed in evolution for millions of years [16]. Newly discovered drugs are accidentally handled by the same biotransformation system. The perception that drug metabolism uses an evolved biotransformation or detoxification system, may facilitate understanding of multiple interactions between endo- and xenobiotics. In the following, a brief overview of Phase I and II enzymes and of uptake and export transporters (Phases 0 and III, respectively) is given; subsequently, examples for coordinate transcriptional regulation of these proteins by nuclear receptors are discussed (Table 1). Finally, functional aspects are summarized.
Section snippets
Phase I enzymes
CYPs (cytochrome P450 enzymes) are major Phase I enzymes, encoded by a large supergene family [16], [17]. Known AHR-controlled CYPs are CYP1A1, CYP1A2 and CYP1B1. Basal expression of CYP1A1 is low, but it is markedly inducible by the AHR in hepatocytes, intestinal epithelium and in vascular endothelium. It is involved in both bioactivation of the carcinogen benzo[a]pyrene and in its first-pass detoxification in the intestinal epithelium [18]. CYP1A2 is constitutively expressed in liver but is
Coordinate regulation of drug biotransformation by AHR, CAR and PXR
Coordinate transcriptional regulation of biotransformation enzymes and transporters appears to enhance the efficiency of homeostatic control of endobiotics and detoxification of dietary xenobiotics.
Functional implications of coordinate regulation
An integrated view of biotransformation is necessary when dealing with in vivo functions. For example, under physiological conditions bile acids are mainly conjugated by sulfation. Under cholestatic conditions, however, bile acid sulfation may be saturated and glucuronidation is taking over. ‘Tight coupling’ of Phase I and II metabolism and conjugate transport by nuclear receptors can be expected in homeostasis and detoxification of endobiotics such as bile acids and bilirubin. To some extent
Conclusions
Coordinate regulation of Phase I and II drug-metabolizing enzymes and conjugate transporters by nuclear receptors PXR, CAR and AHR suggests that these proteins evolved to an integrated biotransformation system. The genetic basis for coordinate regulation may be largely due to common nuclear receptor-binding elements in the regulatory region of target genes. Previously, the AHR gene battery and its linkage with the Nrf2 gene battery was discussed, the latter protecting against oxidative stress
Acknowledgements
We thank Dietrich Keppler (DKFZ Heidelberg, Germany) for critical discussions, and apologize for often citing reviews instead of original studies to reduce the number of references.
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