Introduction

Top Abstract Introduction Inducibility of CYP3A Gene... Characterization of the CYP3A... Species-Specific Induction of... PXR and Its Role... Mechanisms: PXR, CAR, GR,... Future References

Cytochrome P450s (P450¹) constitute a multigene family of hemoproteins responsible for the metabolism of numerous xenobiotics, including therapeutic drugs, environmental chemicals, and dietary constituents, as well as such endogenous compounds as steroids and bile acids (reviewed in Gonzalez et al., 1993). Early studies at both the pharmacological and biochemical levels recognized that this large repertoire of catalytic activities most likely represented multiple enzymes rather than a single isoform. This is clearly the case, with an estimated 50 or more individual P450 enzymes present in any given mammalian species. While some P450 enzymes (e.g., those involved in steroid biosynthesis) exhibit specific catalytic activities, many others display broad, but somewhat overlapping, substrate specificities (Nelson, 1999).

A unique feature of this large family of enzymes is that some members show increased expression upon xenobiotic challenge to the organism. Several decades have passed since the first inducible P450 (now classified as CYP2B) was identified in the liver of rats exposed to phenobarbital (reviewed in Gonzalez et al., 1993). It was postulated that a receptor protein mediated the induction, but this conclusion was confirmed only recently (discussed below). Later, a second unique P450 (now classified as CYP1A), inducible by the arylhydrocarbon, 3-methylcholanthrene, was identified, and its regulation by a ligand-activated receptor described. In the early 1980s, several groups of investigators identified a third distinct form of P450 (now classified as CYP3A), one inducible by steroidal chemicals. These early investigations provided an understanding of many of the pharmacological, biochemical, and biophysical properties of P450 enzymes, including protein structure, substrate specificities, and enzyme kinetics. Through the application of molecular biology, investigators next began to uncover features of P450 gene structure and function that could account for the differences in pharmacologic events described in earlier studies. CYP3A was found to be a gene subfamily composed of multiple forms of CYP3A enzymes as characterized by immunochemistry, catalytic activities, and cDNA cloning and expression.

CYP3As, the liver microsomal enzymes responsible for the oxidative metabolism of numerous clinically used drugs, is known to be induced by a variety of compounds, including naturally occurring and synthetic glucocorticoids (e.g., dexamethasone, Dex), pregnane compounds (e.g., pregnenolone 16-carbonitrile, PCN), and macrolide antibiotics (e.g., rifampicin, RIF) (reviewed in Gonzalez et al., 1993). Multiple forms of CYP3A are present in rat and mouse liver and a single form in rabbit, while four CYP3A genes have been reported for humans (Gonzalez et al., 1993; Domanski et al., 2001). CYP3A cDNAs from various species have been used to probe for patterns of basal and inducible expression, for tissue distribution, and for interspecies differences in gene expression. More recently, techniques and reagents have been developed to isolate and characterize gene promoters and to develop a system to analyze promoters for inducer response elements. These genetic techniques, such as sensitive reporter gene vectors, techniques for transfecting DNA, and the establishment of primary cultures of hepatocytes as a cell model system for analysis of transfected DNA, have contributed greatly to understanding gene structure and regulation, including definition of the CYP3A induction process. These efforts have culminated in exciting recent recognition that nuclear receptors such as those characterized for steroid hormones are agents of CYP3A induction. Thus, the extensive data accumulated from the study of this group of physiologic ligand-activated transcription factors can now be extended to the drug-metabolizing system.

The purpose of this review is to evaluate the current concepts of CYP3A gene induction by xenobiotics, with special emphasis on the emerging role of nuclear receptors in this process. It now seems that there may be extensive cross talk among the nuclear receptor family members, as well as involvement of steroid receptors, such as the glucocorticoid receptor (GR), and other transcription factors. The fascinating question of "what regulates the regulators?" will also be discussed. Finally, we feel it prudent to discuss the implications of induction of CYP3A gene expression for disease states and risk assessment.

	Inducibility of CYP3A Gene Expression

Top Abstract Introduction Inducibility of CYP3A Gene... Characterization of the CYP3A... Species-Specific Induction of... PXR and Its Role... Mechanisms: PXR, CAR, GR,... Future References

In humans, CYP3A4 is believed to play the central role in drug metabolism since it is responsible for the metabolism of the largest number of currently used drugs (Watkins, 1994). Enhanced transcription of CYP3A occurs primarily in the liver and intestines in response to xenobiotic exposure. Agents known to activate CYP3A transcription include steroid hormones having either glucocorticoid or antiglucocorticoid activities, macrolide antibiotics, imidazole antifungal agents, and phenobarbital and phenobarbital-like agents such as polychlorinated biphenyls and organochlorine pesticides (reviewed in Gonzalez et al., 1993). This observation, coupled with the remarkable versatility of CYP3A catalytic activities, creates a potential for drug-drug interactions. Extrapolating data from studies utilizing rodents has proven to be an unreasonable approach for risk assessment because there is a remarkable species-specific induction profile characteristic of this family of P450s (Wrighton et al., 1985). For example, PCN, a strong inducer of CYP3A in the rat, does not induce CYP3A6 in the rabbit, while RIF, a strong inducer of rabbit CYP3A6, is not an inducer in the rat. An understanding of the mechanism underlying this phenomenon required cloning and characterization of the CYP3A promoters and identification of inducer response elements and the factors that interact with these promoter sequences.

	Characterization of the CYP3A Promoter

Top Abstract Introduction Inducibility of CYP3A Gene... Characterization of the CYP3A... Species-Specific Induction of... PXR and Its Role... Mechanisms: PXR, CAR, GR,... Future References

Studies of the rank order of agonist potency and efficacy, of agonist-antagonist relationships, and of the time course of induction of CYP3A in cultured hepatocytes by various steroid hormones led to the conclusion that glucocorticoids (GC) induced CYP3A by a nonclassical GR mechanism probably involving a separate receptor or recognition system (Schuetz and Guzelian, 1984). Verifying the presence of a nonclassical glucocorticoid pathway by detailed molecular studies required the isolation of the cloned genomic DNA encoding the CYP3A² promoter (Burger et al., 1992). The first functional characterization of the rat CYP3A promoter involved transient transfections of various chimeric reporter gene constructs into primary cultures of rat hepatocytes (Burger et al., 1992). These investigators reported that the Dex/PCN response element resided within 164 bp of the start of transcription, and demonstrated that this region of the CYP3A gene maintained the same Dex responsiveness and synergy with PCN that was previously shown in the intact rat liver (Schuetz and Guzelian, 1984). These deletion studies confirmed earlier investigations concluding that the induction of CYP3A apparently utilized a nonclassical glucocorticoid receptor pathway (Schuetz and Guzelian, 1984), in that reporter gene activation occurred only at high doses of GC, and that RU486, a potent GR antagonist, induced CYP3A reporter gene activity, while it blocked GC induction of murine mammary tumor virus promoter-driven reporter activity. The lack of binding sites for the GR in the Dex responsive gene fragment further supported the hypothesis that the CYP3A gene is regulated by steroids through a mechanism that differs from the classical GR-mediated pathway (Schuetz and Guzelian, 1984).

Subsequent studies in primary nonproliferating adult rat hepatocytes (Quattrochi et al., 1995) and in a rat hepatoma cell line (Huss et al., 1996) led to the identification of the rat CYP3A23 Dex/PCN response element. Although both groups of investigators mapped similar response elements, Quattrochi et al. (1995) identified a single 20-bp element (referred to as Fp1, Table 1) as conferring Dex or PCN inducibility, whereas Huss et al. (1996) reported inducible activity only when this same element (referred to as site B or DexRE-2) was linked to an additional upstream sequence (referred to as site C or DexRE-1, Table 1). The discrepancy likely lies in the use of primary hepatocyte cultures versus culture-adapted, continuously replicating hepatoma cell lines that might differ in the availability of transcription factors. Tests of patterns of binding of nuclear proteins to the CYP3A23 Dex/PCN DNA response element gave identical results in the absence or presence of inducers, suggesting that induction occurred via a mechanism in which the unliganded protein factor was constitutively bound to DNA, much as has been reported for the retinoid acid X receptor (RXR) family of nuclear receptors (Evans, 1988). Indeed, the CYP3A23 response element contained two copies of the half-site, AGG(T)TCA, which defines the consensus binding site for this family of nuclear receptors. Furthermore, the GR did not interact with the DNA at the CYP3A23 response element. Patterns of nuclear protein binding to the rat CYP3A23 promoter were similar to those reported by Miyata et al. (1995), who tested the rat CYP3A2 gene. These authors identified three footprints of liver-specific binding proteins, one of which showed DNA sequence homology to the liver-enriched transcription factor HNF-4. Further characterization of the CYP3A23 response element and its binding proteins revealed that "site A" was bound and activated by the nuclear receptor HNF-4, and that the chicken ovalbumin upstream promoter transcription factor (COUP-TF) could interact in vitro with "sites B and C", leading to the conclusion that the GC inducibility of CYP3A genes involves multiple binding sites for members of the nuclear receptor superfamily (Huss and Kasper, 1998; Quattrochi et al., 1998).

	Species-Specific Induction of CYP3A Gene Expression

Top Abstract Introduction Inducibility of CYP3A Gene... Characterization of the CYP3A... Species-Specific Induction of... PXR and Its Role... Mechanisms: PXR, CAR, GR,... Future References

The early observation of interspecies differences in the induction of CYP3A led to studies that addressed whether these differences were due to gene structure or to an endogenous cellular factor. For example, the response element located in the rat CYP3A23 promoter [Fp1 (Quattrochi et al., 1995) or DexRE-2 (Huss et al., 1996)] is composed of two consensus half-sites organized as direct repeats separated by three nucleotides. Subsequent cloning and sequencing of the promoters of the rabbit CYP3A6 and human CYP3A4, CYP3A5, and CYP3A7 genes identified distinct sequences related to the rat CYP3A23 response element (Barwick et al., 1996; Pascussi et al., 1999).

These sequence comparisons could be interpreted in one of two ways: 1) the sequences of the response elements are closely related so that differences in species inducibility are conferred by the same transcriptional activator interacting at these DNA sites, or 2) the sequences are sufficiently different so that a transcriptional activator unique to each species interacts at these sites. To distinguish between these alternatives, Barwick et al. (1996) performed a suitably informative trans-species comparison study in which rat, rabbit, and human CYP3A response elements were transfected into primary cultures of rat or rabbit hepatocytes treated with one of three inducers, Dex, PCN, or RIF. They found that activation of the CYP3A response element-reporter gene acquired the induction characteristics of the cell type; for example, RIF was able to induce the rat CYP3A23 response element when expressed in the rabbit hepatocyte cultures, and PCN induced the rabbit and human CYP3A response elements when expressed in rat cells. These studies clearly established the transcription factor, rather than the CYP3A promoter sequence, as the agent conferring species-specific induction on CYP3A gene transcription.

	PXR and Its Role in Species-Specific Induction of CYP3A

Top Abstract Introduction Inducibility of CYP3A Gene... Characterization of the CYP3A... Species-Specific Induction of... PXR and Its Role... Mechanisms: PXR, CAR, GR,... Future References

PXR and the CYP3A Response Element. Identification of the Dex/PCN response element of the CYP3A genes provided the initial firm evidence for involvement of a nuclear receptor in CYP3A induction. Cloning of PXR (NR1I2), a PCN-activated nuclear receptor in mouse liver, by Kliewer's group at Glaxo Wellcome (Kliewer et al., 1998) confirmed this conclusion. Kliewer's group and others demonstrated that PXR, named the pregnane X receptor because of its strong activation by pregnane compounds, seemed to mediate CYP3A induction not only in mice, but through its homologous counterparts in rat, rabbit, and humans, as well (Bertilsson et al., 1998; Blumberg et al., 1998; Lehmann et al., 1998; Zhang et al., 1999; Savas et al., 2000). The human PXR receptor is also referred to as steroid and xenobiotic-sensing receptor (SXR) (Blumberg et al., 1998) or as the pregnane-activated receptor (Bertilsson et al., 1998). Because there is no generally accepted nomenclature for the human receptor, for the purposes of this review we have chosen to use the term "human PXR". Mutational analysis of the previously identified CYP3A response elements established the PXR binding site of the rodent CYP3A promoter/enhancer as a direct repeat, DR-3 (TGAACTn3TGAACT) (Kliewer et al., 1998), and the rabbit and human CYP3A response elements as everted repeats (TGAACTn6AGGTCA) (ER6; Lehmann et al., 1998) or inverted repeats (IR6; Blumberg et al., 1998). The PXR forms a heterodimer with RXR, a requirement for binding and activation. The heterodimer formed between PXR and RXR can interact with either the DR-3 or ER6/IR6 elements in CYP3A genes.

PXR Ligands. Following the cloning of the PXR from various species, numerous studies identified compounds capable of activating the receptor in a species-specific manner (see Table 2 for examples). The majority of these studies used a cell-based assay system in which CV-1 cells, or other non-liver-derived cells, were transiently transfected with a PXR expression vector and a synthetic oligomer defining the DR-3 or ER6 linked to a viral promoter-driven reporter construct (Bertilsson et al., 1998; Blumberg et al., 1998; Lehmann et al., 1998; Schuetz et al., 1998; Jones et al., 2000; Moore et al., 2000; Savas et al., 2000). For the most part, drugs known to induce CYP3A in vivo were also able to activate the PXR in a species-specific manner. Jones et al. (2000) performed comprehensive comparisons of the PXR from human, rabbit, rat, and mouse using reporter constructs containing two copies of the CYP3A23 DR-3 response element transfected into CV-1 cells. In general, activation of PXR from different species has been in good agreement with the reported induction of CYP3A expression in primary cultures of hepatocytes from these same species. For example, human and rabbit PXR were both efficiently activated by RIF, the antimycotic clotrimazole (CTZ), trans-nonachlor, and phenobarbital (PB); however, rabbit PXR was more sensitive than human PXR to activation by Dex, PCN, cyproterone acetate, and spironolactone. These studies demonstrated that there are clear differences in the activation profiles between human and rabbit receptors. To gain further support for the observations that structurally diverse compounds are ligands of the PXR, Jones et al. (2000) developed a competition radioligand binding assay using [³H]SR12813, a bisphosphonate ester shown to be a potent activator of both the human and rabbit PXR. These experiments showed good agreement between those compounds able to displace [³H]SR12813 from the PXR and those able to activate PXR in transfection assays.

In Vivo Role of the PXR. Transgenic mice have been developed to establish the role of the PXR in vivo (Xie et al., 2000a). Targeted disruption of the mouse PXR gene eliminated the induction of CYP3A by PCN. PXR-null transgenic mice harboring the human PXR gene, when challenged with drugs known to induce human CYP3A such as RIF and CTZ, displayed induced CYP3A mRNA in the liver. Transgenic mice expressing a constitutively active human PXR were shown to develop sustained CYP3A expression, resulting in enhanced protection against challenges of xenobiotic toxicants (Xie et al., 2000a). This "humanized" rodent model system has potential applications for drug and toxicity screening.

	Mechanisms: PXR, CAR, GR, and Others

Top Abstract Introduction Inducibility of CYP3A Gene... Characterization of the CYP3A... Species-Specific Induction of... PXR and Its Role... Mechanisms: PXR, CAR, GR,... Future References

The mechanism by which numerous structurally diverse compounds induce CYP3A expression can be for the most part explained by the PXR. However, several questions remain unanswered. The nuclear receptors COUP-TF and HNF-4 have been implicated as factors interacting with sequences, including those at the Dex/PCN response element, of the rat CYP3A23 promoter. What role they play in the responsiveness of CYP3A to inducers remains to be determined. For example, do these proteins interact directly with the PXR to produce a highly active transcriptional complex? One of the most pressing questions is whether the GR plays a role in CYP3A induction. Dex, an efficacious inducer of CYP3A in rodents and humans, seems to be a relatively weak activator of the PXR, suggesting that the GR may be involved in the induction of CYP3A in these species. It now seems that another nuclear receptor is involved in the regulation of drug-metabolizing enzymes. The CAR has been shown to mediate induction of both CYP3A and CYP2B. And finally, how does the wealth of information gathered over the past several years explain the well established observation of the synergistic effects of GCs and PCN on CYP3A expression?

Factors that Modulate the PXR-Mediated Induction. Recent work has revealed the existence of other proteins that appear to modulate the induction of CYP3A expression. Several transcription factors have been identified that interact with the CYP3A23 promoter and seem to play a role in modulating the expression of CYP3A23 (Huss and Kasper, 1998; Huss et al., 1999; Ogino et al., 1999). Among these are members of the nuclear receptor family, COUP-TF and HNF-4. A postulated mechanism is that COUP-TF competes with the PXR for binding to the DR-3 response element of the CYP3A23 gene or that binding of COUP-TF to the upstream imperfect ER6 (DexRE-1, Table 1) may repress HNF-4-mediated basal expression (Huss and Kasper, 1998). It could be reasoned that if such interactions occur in vivo, then modulation of the induction response would depend on relative amounts of each transcription factor, as well as their affinities for the DNA binding sites. In addition to COUP-TF, an unidentified protein referred to as the "B" protein also may interact with the upstream imperfect ER6, and it was suggested that this protein functions as an accessory factor in cooperation with PXR/RXR and HNF-4 (Huss and Kasper, 1998). The identities of all of the proteins interacting at this upstream element remain unknown, although the possibility exists for the PXR itself to also interact weakly with the upstream imperfect ER6. It may be concluded that binding of PXR to the DR-3 of the CYP3A23 response element is necessary but insufficient for optimal CYP3A23 expression (Quattrochi et al., 1995; Huss et al., 1996). Other factors may interact with other sites in the CYP3A gene or with the PXR at this DR-3 site through protein-protein interactions with the PXR. A summary of the currently postulated relationships of nuclear receptors to the regulation of the rat CYP3A23 promoter is illustrated in Fig. 1.

View larger version (14K): [in this window] [in a new window]   Fig. 1.   Model of CYP3A23 regulation. The model is described in the text. Low dose Dex is 107 M or less, while high dose is 105 M. The underlined sequence, CACGTG, is the putative binding site for upstream stimulatory factor-1.

Role of the Glucocorticoid Receptor in CYP3A Induction. An important unanswered question is whether the GR plays a role in the regulated expression of CYP3A. Some lines of evidence suggest that induction of CYP3A by GCs can also occur through a pathway distinct from the PXR. For example, there is a functional glucocorticoid response element (GRE) in a region of the rat CYP3A23 gene ~2 kb upstream of the PXR/RXR binding site (Fig. 1) (Pereira et al., 1998). In addition, the human CYP3A5 gene promoter contains two GRE half-sites, separated by 160 bp, that confer GC responsiveness to reporter genes (Schuetz et al., 1996). Conversely, studies in a GR-null mouse model suggest the opposite. Schuetz et al. (2000), using mice containing a targeted disruption of the GR to test its role on induction of CYP3A, found that CYP3A induction by GC, RU486, or RIF can occur in the absence of the GR. However, since the concentrations of Dex used in these studies, 50 mg/kg, may have activated the PXR, it is not possible to discern whether the induction of CYP3A in the wild-type or null mice is mediated through the PXR. Moreover, inasmuch as dose response data were apparently not obtained, this study does not exclude the possibility of involvement of the GR to augment the induction process. In fact, recent studies demonstrating the ability of Dex to increase PXR levels in hepatoma cell lines and primary hepatocytes (Huss and Kasper, 2000; Pascussi et al., 2000a) lend support to the concept that the GR plays a role in the induction process (discussed below). Finally, it should be noted that the mouse CYP3A promoters have not been characterized as extensively as the rat or human promoters. Thus, the possibility that the GR plays a role in the induction of rat CYP3A23 and/or human CYP3A4 cannot be excluded. Indeed, cotransfected GR was shown to enhance the GC induction of a CYP3A4 reporter gene construct in transfected HepG2 cells (El-Sankary et al., 2000).

Cross Talk: PXR and CAR. Early studies of CYP3A induction profiles established that the induction of CYP3A and CYP2B by PB occurred through distinct mechanisms (Kocarek et al., 1990). The cloning of both PXR and CAR has provided insight into this divergent regulatory mechanism. CAR binds DNA as a heterodimer with RXR and activates gene transcription in a constitutive manner; however, CAR-mediated transcriptional activation can be inhibited by androstane metabolites (reviewed in Honkakoski and Negishi, 2000). The CAR/RXR heterodimer interacts with the PB response element module (PBREM) located in CYP2B promoters of rat, mouse, and human genes, and mediates PB-inducible gene transcription. The PBREM contains a nuclear factor 1 binding site flanked by two nuclear receptor binding sites composed of imperfect direct repeats of half-sites spaced by four nucleotides (DR-4 motif). The mechanism by which PB derepresses CAR is presently unknown, but may involve direct ligand binding. Phenobarbital is also a fairly strong activator of the human PXR, but it has little or no effect on the rodent PXR (Jones et al., 2000; Xie et al., 2000a). Each PB-activated receptor can then interact with its own recognition site (i.e., PXR for the DR-3/ER6 in CYP3A promoters, and CAR for the PBREM in CYP2B promoters). However, CAR was shown to bind to and activate a reporter gene through the CYP3A4 ER6 response element, thus establishing the possibility for cross talk between CAR and PXR (reviewed in Honkakoski and Negishi, 2000).

Synergy: Who Are the Players? A final question concerns the identity of the factors mediating synergy. The GR has been implicated in playing a role in the previously reported synergistic interaction between PCN and Dex for induction of CYP3A (Schuetz and Guzelian, 1984). An open possibility is that the GR could interact with the PXR promoter transcription complex through protein-protein interactions. Another suggestion is that the GRE found upstream of the PXR/RXR binding site of the rat CYP3A1 gene might play a role in the synergistic effects of Dex and PCN on CYP3A expression (Pereira et al., 1998). Recently, it was shown that Dex treatment of rat hepatoma cells and primary cultures of human hepatocytes increased levels of both PXR and RXR (Huss and Kasper, 2000; Pascussi et al., 2000a). It was concluded from these studies that the effect of Dex on PXR mRNA accumulation was most likely through direct activation of the GR. Therefore, another possibility for the reported synergy is that physiological levels of GC may activate the GR and increase the production of both PXR and RXR proteins, which in turn can further function as transcriptional regulators of CYP3A. This idea would require the levels of both nuclear receptors to be rate limiting in the hepatocyte, and evidence suggests that this may be the case in vivo, at least for the PXR (Zhang et al., 1999). Cloning of the PXR and RXR promoters and the identification of functional GREs within the promoters would lend support for this theory.

	Future

Top Abstract Introduction Inducibility of CYP3A Gene... Characterization of the CYP3A... Species-Specific Induction of... PXR and Its Role... Mechanisms: PXR, CAR, GR,... Future References

The cloning of the PXR and its involvement in CYP3A induction represents a critical advance in the field of drug metabolism. Its demonstrated interaction with structurally diverse chemicals provides an explanation for much of the pharmacology of this P450 gene subfamily. As with many of the nuclear receptors, the PXR likely will be found to play a role in human physiology, outside that of drug metabolism. If so, this will surely lead to studies directed at certain disease states and risk assessment. For example, Pascussi et al. (2000b) demonstrated that interleukin-6 negatively regulates both PXR and CAR, suggesting that this provides direct evidence for the molecular mechanism underlying one of the earliest observations: that xenobiotic and drug metabolism is markedly impaired during inflammation and infections. Furthermore, endocrine functions may be altered by the interaction of endocrine-disrupting chemicals, such as phthalic acid and nonylphenol, recently shown to activate the mouse PXR (Masuyama et al., 2000). It seems likely that CYP3A plays one or more essential roles in body homeostasis, since to date this enzyme system has been found in every human liver examined. However, there is no comparable database on the possibility that CYP3A induction itself could be polymorphic. Considering the growing evidence that CYP3A induction may be more complex than initially believed, involving not only the PXR, which itself may be under inducible regulatory control, but also other nuclear receptors and response-modifying proteins, a fruitful area of future research will be exploring human variation in CYP3A induction.

Linda Quattrochi received the Ph.D. degree in biochemistry from the University of Alabama, Birmingham, in 1982. Her initial interest in the cytochrome P450s began in marine organisms when she took a postdoctoral position at the University of Georgia, Skidaway Institute of Oceanography, Savannah, with Dr. Richard Lee.

In 1984, Dr. Quattrochi moved to the laboratory of Dr. Robert Tukey at the Cancer Center of the University of California, San Diego, where she began molecular cloning of human cytochrome P450 genes. As a result of this and related work, she has had a career-long interest in the mechanisms that regulate human CYP1A2 gene expression. Dr. Quattrochi's most recent research has emphasized examination of dietary flavonoids for their ability to alter P450 gene expression. In 1993, she joined the faculty at the University of Colorado Health Sciences Center in Denver where she is now an Associate Professor of Medicine. In addition to her CYP1A2 research, she has collaborated on a number of projects with Dr. Philip Guzelian in studies of CYP3A gene regulation.

Philip S. Guzelian is Professor of Medicine and Pharmacology at the University of Colorado Health Sciences Center, Denver, and Chief of the Section of Medical Toxicology. For 17 years before moving to Colorado, he was Professor of Medicine in the Departments of Internal Medicine, Pathology, and Pharmacology and Toxicology at the Medical College of Virginia/Virginia Commonwealth University, Richmond.

Dr. Guzelian is board-certified in Internal Medicine, has been elected to membership in such organizations as the Society of Toxicology and the Association of American Physicians, has served on committees of the National Academy of Sciences, the USEPA, and the National Institutes of the Environmental Health Sciences. He has authored or co-authored over 150 abstracts, peer-reviewed articles, or book chapters in basic and clinical research studies involving molecular mechanisms by which the liver responds to the presence of foreign substances. Because of his contributions in medicine and basic science and toxicology, he received the 1984-1989 Burroughs Wellcome Toxicology Scholar Award given through the Society of Toxicology.