Constitutive expression of hepatic cytochrome P450 genes (original) (raw)
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Current Drug Metabolism
Numerous members of the cytochrome P450 (CYP) superfamily are induced after exposure to a variety of xenobiotics in human liver. We have gained considerable mechanistic insights into these processes in hepatocytes and multiple ligand-activated transcription factors have been identified over the past two decades. Families CYP1, CYP2 and CYP3 involved in xenobiotic metabolism are also expressed in a range of extrahepatic tissues (e.g. intestine, brain, kidney, placenta, lung, adrenal gland, pancreas, skin, mammary gland, uterus, ovary, testes and prostate). Since the expression of the majority of the isoforms appears to be very low in the extrahepatic tissues in comparison with predominant expression in adult liver, the role of the enzymes in overall biotransformation and total body clearance is minor. However, basal expression and up-regulation of extrahepatic CYP enzymes can significantly affect local disposition of xenobiotics or endogenous compounds in peripheral tissues and thus modify their pharmacological/toxicological effects or affect absorption of xenobiotics into systemic circulation. The goal of this review is to critically examine our current understanding of molecular mechanisms involved in induction of xenobiotic metabolizing CYP genes of human families CYP1, CYP2 and CYP3 by exogenous chemicals in extrahepatic tissues. We concentrate on organs such as the intestine, kidney, lung, placenta and skin, which are involved in drug distribution and clearance or are in direct contact with environmental xenobiotics. We also discuss single nucleotide polymorphisms (SNPs) of key CYPs, which at the level of transcription affect expression of the genes in the extrahepatic tissues or are associated with some pathophysiological stages or disorders in the organs.
Regulation of drug-metabolizing human cytochrome P450s
Acta Chimica Slovenica, 2008
Drug-metabolizing enzymes, primarily cytochrome P450 (P450) enzymes, play central role in biotransformation, detoxication and elimination of various, structurally diverse xenobiotics. The expression of P450s is controlled by specific receptors capable of sensing xenobiotics, including notably aryl hydrocarbon receptor, a member of the Per/Arnt/Sim family of transcription factors, pregnane X receptor, constitutive androstane receptor, and peroxisome proliferators activated receptor, members of the nuclear receptor superfamily, as well as classical steroid receptors such as glucocorticoid receptor and vitamin D receptor. Because these receptors can interact with and be activated by xenobiotics, they are often designated as xenosensors. The xenobiotic signaling pathways appear to be embedded within a tangle of regulatory networks and the expression of P450s is regulated not only by xenobiotics, but also by numerous endogenous compounds (corticoids, hormones, cytokines, bile salts) frequently increased in pathophysiological conditions. Conversely, xenobiotics appear to affect the expression of genes controlling endogenous signaling pathways. The ability of nuclear receptors to control the transcription of several distinct genes suggests the existence of a complex regulatory network of metabolism of xenobiotics and endogenous compounds. This sophisticated network providing adaptive responses to many exogenous stimuli, e.g. drug treatment or exposure to chemical pollutants is discussed in this review.
Hepatic cytochrome P450 activity, abundance, and expression throughout human development
Drug metabolism and disposition: the biological fate of chemicals, 2016
Cytochrome P450s are oxidative metabolic enzymes that play critical roles in the biotransformation of endogenous compounds and xenobiotics. The expression and activity of P450 enzymes varies considerably throughout human development; the deficit in our understanding of these dynamics limits our ability to predict environmental and pharmaceutical exposure effects. In an effort to develop a more comprehensive understanding of the ontogeny of P450 enzymes, we employed a multi-omic characterization of P450 transcript expression, protein abundance, and functional activity. Modified mechanism-based inhibitors of P450s were used as chemical probes for isolating active P450 proteoforms in human hepatic microsomes with developmental stages ranging from early gestation to late adult. High-resolution liquid chromatography mass spectrometry was used to identify and quantify probe-labeled P450s allowing for a functional profile of P450 ontogeny. Total protein abundance profiles and P450 rRNA was...
Functionally Conserved Xenobiotic Responsive Enhancer in Cytochrome P450 3A7
Biochemical and Biophysical Research Communications, 2001
Nuclear receptors CAR and PXR play a key role in cytochrome P450 gene induction by xenobiotics. Human cytochrome P450 3A7 (CYP3A7) is expressed from early in gestation until the perinatal period, when there is a switch in expression to CYP3A4. Here we demonstrate that a PXR and CAR responsive enhancer is located approximately 8 kb upstream of the proximal CYP3A7 promoter. This distal xenobiotic responsive enhancer module (XREM) is conserved with the XREM of CYP3A4. Interestingly, not only the XREM, but also the entire promoters exhibit 90% sequence identity up to ؊8.8 kb, indicating a close evolutionary distance. We propose that the promoters have coevolved to functionally conserve P450 gene induction in response to xenobiotics through CAR and PXR. Thus, nuclear receptors for xenobiotics may not only play a role to provide a survival advantage during adulthood, but also to protect the embryo against endogenous and exogenous toxins.
Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver
Genome Research, 2010
Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.
Identification of multiple regulatory elements on the human cytochrome P450IA1 gene
Carcinogenesis, 1988
To examine the transcriptional regulation of the human cytochrome P450IA1 gene, a 3574 bp fragment containing 1140 bp of 5' flanking sequences, exon 1 (leader information only), intron 1, and the leader sequences from exon 2, was cloned upstream of the reporter gene, chloramphenicol acetyltransferase, and used to transfect the human hepatoma cell line, HepG2. In transient expression assays, treatment of the transfected cells with 3-methylcholanthrene, benzo[a]pyrene or 2,3,7,8-tetrachlorodibenzofuran was shown to induce the expression of chloramphenicol acetyltransferase 10-fold. Previous studies by other investigators have identified a xenobiotic responsive element at greater than 800 bp 5' to the cap site in the mouse and rat cytochrome P450IA1 gene. In the current report, deletion of sequences from the 5' side of the P450IA1 fragment, as well as internal deletions, were used to identify at least three additional regulatory elements. A second positive, 3-methylcholanthrene responsive element was localized to sequences between -49 and -560 in addition to confirming the location of a similar element between -831 and -1140. These elements flank a potent negative regulatory element that has been conserved between the rat, mouse and human P450IA1 genes and also exhibits significant sequence identity with one of the negative control elements of the human c-Ha-ras1 proto-oncogene. Deletion of the negative control element clearly demonstrated that the fragments containing xenobiotic responsive elements also possess positive, constitutive control activity. A fourth element located within intron 1 was shown to potentiate the activity of 3-methylcholanthrene when the cells were treated simultaneously with the glucocorticoid agonist, dexamethasone.
Cytochromes P450 and metabolism of xenobiotics
Cellular and Molecular Life …, 2001
Cytochromes P450 (henceforth P450s) are involved in a variety of metabolic and biosynthetic processes. The number of known P450 enzymes exceeds 1000, while the endogenous substrates of most of them remain unknown. All P450 enzymes exhibit similarity in their structure and general mechanism of action; however, there are significant differences in the detailed function of individual enzymes as well as in the structures and properties of their active sites. This review discusses the pro
Advances in Pharmacology, 2015
The liver is a unique organ in the body as it has significant roles in both metabolism and innate immune clearance. Hepatocytes in the liver carry a nearly complete complement of drug metabolizing enzymes, including numerous cytochrome P450s. While a majority of these enzymes effectively detoxify xenobiotics, or metabolize endobiotics, a sub-portion of these reactions result in accumulation of metabolites that can cause either direct liver injury or indirect liver injury through activation of inflammation. The liver also contains multiple populations of innate immune cells including the resident macrophages (Kupffer cells), a relatively large number of natural killer cells, and blood-derived neutrophils. While these cells are primarily responsible for clearance of pathogens, activation of these immune cells can result in significant tissue injury during periods of inflammation. When activated chronically, these inflammatory bouts can lead to fibrosis, cirrhosis, cancer or death. This Chapter will focus on interactions between how the liver processes xenobiotic and endobiotic compounds through the cytochrome P450 system, and how these processes can result in a response from the innate immune cells of the liver. A number of different clinically relevant diseases, as well as experimental models, are currently available to study mechanisms related to the interplay of innate immunity and cytochrome P450 mediated metabolism. A major focus of the chapter will be to evaluate currently understood mechanisms in the context of these diseases as a way of outlining mechanisms that dictate the interactions between the P450 system and innate immunity.