©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Xenobiotic-inducible Transcription of Cytochrome P450 Genes (*)

Michael S. Denison (1) James P. Whitlock , Jr. (2)

From the  (1)Department of Environmental Toxicology, University of California, Davis, California 95616 and the (2)Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305-5332

INTRODUCTION
Aromatic Hydrocarbon-inducible Cytochrome P450s
Phenobarbital-inducible Cytochrome P450s
Peroxisome Proliferator-inducible Cytochrome P450s
Steroid-inducible Cytochrome P450s
Conclusion
FOOTNOTES
REFERENCES


INTRODUCTION

Numerous foreign chemicals (xenobiotics) confront us daily; such compounds often are lipophilic and may accumulate to toxic levels unless they are metabolized to water-soluble products that can be readily excreted. A cytochrome P450 enzyme(s) often catalyzes the initial step in such detoxification pathways. Multiple forms of cytochrome P450 exist; these enzymes are notable for their broad and overlapping substrate specificities. Although P450s usually mediate detoxification reactions, under some circumstances they activate their substrates to carcinogenic, mutagenic, and/or cytotoxic products. They also contribute to the oxidative metabolism of endogenous hormones, fatty acids, and cytokines(1, 2, 3, 4, 5) .

Some cytochrome P450 genes are expressed constitutively, while others (particularly those involved in xenobiotic metabolism) are inducible. In many cases, inducers are also substrates for the induced enzymes; therefore, P450 activities remain elevated only as needed. Enzyme induction usually enhances detoxification; thus, under most conditions, induction is a protective mechanism(3, 5, 7) . Induction most often occurs at the level of transcription(6, 7) . Table 1lists the major xenobiotic-inducible cytochrome P450s and some of their substrates.



The inducible cytochrome P450 enzymes represent interesting experimental systems for analyzing the mechanisms by which small molecules enhance the transcription of specific genes. Such knowledge can provide insights into gene regulation that are of relatively broad interest. Here, we briefly summarize the mechanisms by which xenobiotics induce cytochrome P450 gene transcription.


Aromatic Hydrocarbon-inducible Cytochrome P450s

Polycyclic aromatic hydrocarbons, such as the carcinogens 3-methylcholanthrene (3-MC) (^1)and benzo(a)pyrene, are prototypical inducers of several P450s, most notably P4501A1/1A2 and 1B1(6, 7, 8, 9, 10, 11) . Nuclear ``run-on'' experiments have revealed that induction primarily reflects an increase in the rate of transcription of these genes(8, 9, 10, 11) , although posttranscriptional effects on P4501A2/1B1 have been reported(3, 12) . Our understanding of cytochrome P450 induction by aromatic hydrocarbons is based largely upon analysis of P4501A1 gene transcription.

The Ah Receptor

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an unusually potent inducer of P4501A1 (up to 30,000 times more potent than 3-MC (13) ). Poland et al.(13) showed that mouse liver contained a protein that bound TCDD saturably, reversibly, and with high affinity and, thus, had the ligand binding properties of a receptor. The protein has been designated as the ``Ah receptor'' because it binds other aromatic hydrocarbons (such as 3-MC and benzo(a)pyrene) in addition to TCDD. Biochemical and genetic evidence implicates the Ah receptor in the induction of CYP1A1 transcription. For example, structure-activity studies reveal a correlation between receptor binding affinity and potency as an inducer. Furthermore, genetic studies in inbred mouse strains reveal quantitative differences in responsiveness to TCDD, and the same genetic locus governs both TCDD binding and enzyme induction(13) .

The AhR's structure, deduced from its cDNA sequence, reveals several features: 1) a basic helix-loop-helix (bHLH) domain; 2) two regions, designated as ``PAS,'' because of their homology with the regulatory proteins Per, Arnt, and Sim; 3) a glutamine-rich region(14, 15) . Mutational analyses imply that the bHLH domain is important for protein-protein interactions and for binding to DNA(14, 16, 17) . The PAS domains appear necessary for protein-protein interactions and for ligand binding, while the C-terminal half of the AhR is required for transactivation(14, 16, 17, 18) . The in vitro translated receptor does not bind strongly to DNA, even in the presence of TCDD; acquisition of DNA binding capability requires that the receptor heterodimerize with the Arnt protein (see below)(14, 15, 16) . Additional proteins that may participate with the AhR in the induction response have recently been identified(8, 19, 20, 21, 22) . The deduced sequence of AhR reveals that it is a novel type of ligand-activated transcription factor, distinct from those described previously.

The Arnt Protein

Hankinson (15) identified a cDNA that complements the defect in cells that fail to respond to TCDD, even though their AhR is normal. Hankinson (15) designated the corresponding protein as ``Arnt'' (for Ah receptor nuclear translocator). Its deduced amino acid sequence reveals that Arnt has an organization that is similar to AhR: 1) a bHLH domain; 2) two PAS homologies; 3) a glutamine-rich region. Mutational studies implicate the bHLH region in DNA binding and heterodimerization with AhR; the C-terminal region provides a transactivation function(15, 18, 23, 24) . The Arnt protein does not bind TCDD and does not bind to DNA in the absence of liganded AhR(15) . The data imply that Arnt heterodimerizes with liganded AhR to generate an active, enhancer binding transcription factor.

Activation of Transcription

Recombinant DNA and transfection experiments revealed the presence of a TCDD-inducible, AhR-dependent, and Arnt-dependent transcriptional enhancer and a transcriptional promoter upstream of the CYP1A1 gene(8, 15) . The enhancer participates in inducible, AhR-dependent, and Arnt-dependent protein-DNA interactions, as expected for the binding of the AhRbulletArnt heterodimer to DNA. The heterodimer recognizes a specific nucleotide sequence (which has been designated as a xenobiotic-responsive element or a dioxin-responsive element); furthermore, AhRbulletArnt binds within the major DNA groove and bends the DNA in vitro near the site of the protein-DNA interaction(8) .

Chromatin Structure

Studies in intact cells reveal that the inactive enhancer appears relatively inaccessible to DNA-binding proteins in vivo. Exposure to TCDD leads to the rapid occupation of multiple binding sites for AhRbulletArnt(8, 15) . The data suggest that AhRbulletArnt activates transcription via a mechanism that does not require other enhancer-binding proteins. In uninduced cells, constitutively expressed, general transcription factors fail to bind to the CYP1A1 promoter. However, in the presence of TCDD, rapid occupation of protein-binding sites on the promoter is observed(8) . Thus, the binding of AhRbulletArnt to the enhancer facilitates the binding of transcription factors to the promoter. The inactive enhancer/promoter region assumes a nucleosomal configuration with a nucleosome specifically positioned at the promoter. The nucleosomal organization provides an explanation for the inaccessibility of the CYP1A1 regulatory region in uninduced cells. The loss of nucleosomes at the promoter plausibly accounts for the increase in CYP1A1 transcription that occurs in induced cells(8) .

Future Research

CYP1A1 induction constitutes an interesting system for analyzing the mechanism by which bHLH transcription factors alter chromatin structure and enhance gene expression; the results of such analysis may be of relatively broad interest. Molecular genetic techniques are being used to study the functional organization of AhR and Arnt and to identify and characterize additional proteins that may participate in the induction response. In addition, CYP1A1 induction is a prototype for the analysis of the mechanism by which bHLH transcription factors alter chromatin structure and enhance gene expression. CYP1A1 induction provides a model for other TCDD-inducible cytochrome P450 genes, like CYP1A2 and CYP1B1. Induction of these genes is AhR-dependent, largely transcriptional, and, at least in the case of the CYP1A2 gene, it involves dioxin-responsive transcriptional enhancers(7, 9, 10, 11, 12) .

Several factors have facilitated the mechanistic analyses of cytochrome P4501A1 induction: (a) uninduced activity (background) is low and induced activity (signal) is high; (b) induction occurs in cells in culture; (c) a high potency, non-metabolized inducer (TCDD) is available; (d) induction exhibits a genetic polymorphism in mice; (e) methods are available to isolate induction-defective cells, which enables genetic analyses. As described in more detail in subsequent sections, analyses of the induction of other cytochrome P450 enzymes suffer from the lack of one or more of these factors. Therefore, for other cytochrome P450 enzymes, our understanding of the induction mechanism is less complete than it is for cytochrome P4501A1.


Phenobarbital-inducible Cytochrome P450s

The induction of drug- and steroid-metabolizing enzyme activity by phenobarbital (PB) was one of the seminal observations leading to scientific interest in cytochrome P450. PB induces several forms of cytochrome P450 (Table 1) as well as other xenobiotic-metabolizing enzymes. In addition, compounds that are structurally unrelated to PB (e.g. 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), certain polychlorinated biphenyls, and others) induce a similar pattern of enzyme activities and are considered to be ``PB-like''(6, 7, 25) .

In rat liver, PB rapidly increases the rate of transcription of the CYP2B1/2 genes(6, 25) . In chick embryo liver, PB rapidly induces CYP2H1 and CYP2H2, which are related structurally to CYP2B1/2, by a combination of transcriptional and post-transcriptional mechanisms(5, 6, 25) . In Bacillusmegaterium, PB induces fatty acid monooxygenases (CYP102 and CYP106) by increasing transcription of the corresponding genes(26) .

Because PB induces cytochrome P450 transcription in bacteria, birds, and mammals, we might expect the induction mechanism to be highly conserved; however, this is not so. For example, in rat hepatocytes, PB induces CYP2B1/2 and CYP3A by different mechanisms, which are distinguishable by their sensitivity to cycloheximide (ongoing protein synthesis is required for induction of CYP2B1/2 but not that of CYP3A(25) ). Similar differences have also been reported in other systems(25) .

A Phenobarbital Receptor?

The structural diversity among PB-like inducers is difficult to reconcile with the existence of a specific receptor for these compounds. Studies using radiolabeled PB as a ligand have failed to detect a specific PB-binding protein. A potent inducer, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene, appeared potentially useful for ligand binding studies; however, it is active in mice, but not in guinea pigs or rats. Therefore, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene probably does not act by a mechanism identical to that of PB (7, 25) .

Activation of Transcription

In B. megaterium, the upstream regulatory region of the barbiturate-inducible CYP102 (BM-3) gene contains a 17-base pair element (designated as the ``Barbie Box''), which regulates the response to PB(26, 27, 28) . Transfection experiments in primary rat hepatocytes demonstrated that a Barbie Box sequence could confer PB inducibility upon a heterologous gene; a mutant consensus sequence was inactive(29) . Consensus Barbie Box sequences have been identified upstream of the bacterial CYP102 and CYP106 (BM-1) genes, the rat CYP2B1/2 and CYP3A2 genes, and other PB-responsive genes(27, 28) . The consensus sequence bound proteins from both bacteria and rat liver nuclei in a PB-dependent manner in vitro(26, 27, 28, 29) . Notably, PB treatment reduced the binding of the bacterial proteins to DNA but increased the binding of the mammalian proteins. These findings imply the existence of a PB-dependent protein(s) that binds to DNA near the promoter region of PB-responsive cytochrome P450 genes(26, 27, 28, 29, 30) . Whether the protein(s) is expressed constitutively or is induced by PB is unresolved, and its function remains to be determined.

Shaw et al.(31) have identified a PB-responsive DNA region upstream of the CYP2B1 and CYP2B2 genes. They also demonstrated that PB responsiveness was influenced by glucocorticoids and suggested that PB might act indirectly by causing the accumulation of an endogenous steroid. A PB-responsive element(s) has also been localized to a region between -5.9 and -1.1 kilobases upstream of the start site of CYP2H1 transcription(25) . Omiecinski and colleagues (32) used transgenic mice to localize a PB-responsive DNA regulatory element(s) within the -0.8 to -19-kilobase region upstream of the transcription start site of the rat CYP2B2 gene(32) . The properties of these PB-responsive DNA elements remain to be determined.

Future Research

We understand relatively little about the mechanism by which PB and PB-like chemicals induce cytochrome P450 gene expression. The lack of convenient PB-responsive cell culture systems, as well as the lack of genetic polymorphisms in PB responsiveness, have hindered mechanistic analyses. Recently developed primary or continuous cell lines that respond to PB have been reported(25) , and their utility in mechanistic analyses of PB action is being exploited(25, 29, 31) . Identification of PB-responsive elements by transfection provides an avenue for purification and cloning of the cognate transactivating factors. The lack of structural similarity among PB-like inducers is difficult to reconcile with the concept of a specific ``PB receptor.'' It seems more likely that PB-like compounds act indirectly to induce cytochrome P450 gene transcription. Thus, the question of PB responsiveness remains an intriguing experimental issue for the future.


Peroxisome Proliferator-inducible Cytochrome P450s

Several structurally dissimilar compounds, including fibrate hypolipidemic drugs, phthalate ester plasticizers, and halogenated aromatic solvents induce peroxisome proliferation in mammalian liver. This response involves increased peroxisomal beta-oxidation of fatty acids, as well as induction of microsomal lauric acid -hydroxylase activity, which is catalyzed by cytochrome P4504A1. The induced enzymes may play a role in the metabolism of long chain fatty acids(33) .

In rat liver, clofibrate rapidly increases CYP4A1/6 gene transcription (33, 34) . Likewise, peroxisome proliferators rapidly increase the transcription rates of the genes for fatty acyl-CoA oxidase (ACO) and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, components of the peroxisomal fatty acid beta-oxidation pathway(35, 36) .

Peroxisome Proliferator-activated Receptor

The transcriptional nature of the induction response led to the hypothesis that peroxisome proliferators (PPs) act via a nuclear protein related to steroid hormone receptors. Cloning and functional analyses of ``orphan'' receptor cDNAs led to the identification of a ``peroxisome proliferator-activated receptor'' (PPAR) cDNA, which mediates the biological response to PPs(35, 36) . Certain androgens and fatty acids can also activate rat liver PPAR(37, 38) . Direct binding of ligands to the PPAR has not been demonstrated; furthermore, the lack of structural similarity among PPs suggests that they might act indirectly to induce gene transcription.

Activation of Transcription

Tugwood et al.(39) identified a DNA domain upstream of the ACO gene that conferred PP responsiveness upon a reporter gene; electrophoretic mobility shift experiments suggested that the PPAR binds to its cognate response element in vitro. Johnson and co-workers (34) identified a functional PP-responsive element upstream of the rabbit cytochrome P4504A6 gene; they subsequently demonstrated its specific interaction with an activated PPARbulletRXR heterodimer. These observations imply that the PPAR acts via a mechanism analogous to that described for the steroid/thyroid/retinoid family of nuclear receptors.

PPs induce the transcription of the cytochrome P4504A and ACO genes; however, the induction mechanisms for the two genes may differ. For example, studies in rat hepatocytes imply that induction of CYP4A1/6 transcription is a primary response to PPs and precedes the induction of ACO transcription, which is a secondary response(40) . Furthermore, mechanism-based inactivators of cytochrome P4504A1 inhibited the induction of ACO but not the induction of P4504A1. In addition, hexadecanedioic acid, a long chain fatty acid formed by cytochrome P4504A1, induced ACO but not P4504A1(41) . These data suggest that induction of the cytochrome P4504A1 enzyme and the resultant generation of long chain fatty acids are required for the subsequent induction of peroxisomal beta-oxidation enzymes.

Future Research

The lack of structural similarity among PPs raises the question as to the identity of the ligand(s) that actually binds to the PPAR. Identification of such ligands might provide new insights into the contributions of the PPAR, peroxisomal enzymes, and cytochrome P4504A enzymes to lipid metabolism. In some cases, PPAR-dependent and other pathways may converge to generate novel patterns of gene regulation. For example, the PPAR can form heterodimers with another member(s) of the nuclear receptor family, permitting the target gene to respond to a more diverse set of chemical signals(35, 36) . Future studies in this area may provide new insights into the mechanisms by which PPs produce their biological effects.


Steroid-inducible Cytochrome P450s

In the early 1970s, Selye (42) observed that the ``catatoxic'' steroid, pregnenolone-16alpha-carbonitrile (PCN), induced hepatic xenobiotic-metabolizing enzyme activity. Subsequent studies demonstrated that PCN induced a novel form of cytochrome P450(7) . More recently, others have reported that PCN or high doses of dexamethasone or anti-glucocorticoids induce additional forms of cytochrome P450 (Table 1). The PCN-inducible enzymes, designated as the cytochrome P4503A family, metabolize a variety of substrates, including testosterone and numerous drugs(6, 7) .

Mechanism of Induction

Exposure of rats either to PCN or to high doses of dexamethasone leads to an increased rate of hepatic cytochrome P4503A gene transcription(6, 7) . Guzelian and co-workers (43) have identified a dexamethasone/PCN-responsive DNA element between -220 and -56 upstream of the CYP3A1 gene. However, the exact cis-acting element(s) responsible for the induction response remains to be determined. Studies with a variety of steroid hormone analogs indicate that induction of cytochrome P4503A, 2B1/2, and 2C6 occurs in response to dexamethasone and glucocorticoid receptor antagonists and thus does not involve a known steroid receptor(7, 43, 44) .

Future Research

The recent development of cell culture systems in which the CYP3A gene(s) responds to steroids, phenobarbital, and other inducers should facilitate future analyses of the induction mechanism(45) . The discovery of more potent inducers and the development of a photoaffinity ligand might permit the identification of the receptor that mediates induction. Identification of PCN-responsive elements by transfection provides an avenue for purification and cloning of the cognate transactivating factor(s). Isolation of induction-defective cells would allow the application of genetic techniques to the study of this interesting system.


Conclusion

The cytochrome P450 superfamily consists of over 150 P450 genes present in a variety of organisms(46) . It has been proposed that the genes evolved during ``animal-plant warfare'' as a mechanism by which animals protected themselves from dietary and environmental toxicants (47) . Induction is likely to be advantageous from an evolutionary standpoint, allowing enhanced detoxification following exposure to xenobiotics. On the other hand, it is unclear whether the regulatory pathways evolved specifically to deal with dietary and environmental xenobiotics or whether they evolved from regulatory pathways already present in the cell for other reasons. For example, cytochrome P450 gene regulation may have evolved as a mechanism to maintain metabolic homeostasis with respect to endogenous lipophilic substrates (e.g. steroids, fatty acids, etc.). If true, this scenario would predict the existence of endogenous ligands that regulate cytochrome P450 transcription. Identification of such ligands would generate a better understanding of the biochemical pathways by which cells recognize and respond to chemical stimuli.


FOOTNOTES

*
This minireview will be reprinted in the 1995 Minireview Compendium, which will be available in December, 1995.

^1
The abbreviations used are: 3-MC, 3-methylcholanthrene; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; bHLH, basic helix-loop-helix; PB, phenobarbital; ACO, fatty acyl-CoA oxidase; PP, peroxisome proliferator; PPAR, peroxisome proliferator-activated receptor; PCN, pregnenolone-16alpha-carbonitrile; AhR, aromatic hydrocarbon receptor; Arnt, AhR nuclear translocator.


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