David J. Waxman
Professor of Cell
and Molecular Biology, Dept of Biology
Molecular endocrinology and cell signaling; Cancer gene therapy and pharmacology; Liver genes and transcriptional control; Orphan receptors and responses to foreign chemicals
Humans, like other mammals, are exposed to a large number of toxic foreign chemicals, many of which are lipophilic and have a tendency to persist in fatty tissues. In response to this environmental challenge, mammals have evolved a large number of genes which encode cytochromes P450 and other enzymes that oxygenate lipophilic foreign compounds. Expression of these genes is controlled by a complex array of molecular regulatory circuits that respond to varying physiological conditions and changes in hormonal and environmental stimuli. In addition to metabolizing foreign chemicals, P450 enzymes hydroxylate physiological substrates, such as steroid hormones, arachidonic acid and cholesterol, which both compete with drug and other foreign chemical substrates and can regulate P450 metabolism through the modulation of P450 gene expression.
A major goal of our laboratory is to elucidate these metabolic processes at both the biochemical, molecular regulator and gemomic levels. One of our research projects involves the regulation of liver P450 gene expression by the temporal pattern of pituitary growth hormone (GH) release. A second important goal of our laboratory is to identify ways through which our understanding of P450 biochemistry and gene regulation may be applied to improve human health. These efforts are exemplified by our development of cytochrome P450 as a model for cancer gene therapy using drug-susceptibility genes. P450 genes have great promise for applications designed to enhance the sensitivity of tumor cells to cancer chemotherapeutic drugs.
Current areas of major research emphasis include:
1) liver P450 gene
regulation by endocrine factors;
These studies require an interdisciplinary approach, with emphasis on techniques drawn from molecular biology, cell biology, biochemistry and pharmacology. Model systems utilized include intact animal models (rat liver model, gene knockout mice, immunodeficient scid mice), cell culture models, and in vitro biochemicals studies, including the use of human liver microsomes and cDNA-expressed enzyme systems. Primary emphasis is placed on the following areas of research:
Endocrine control of hepatic P450 gene expression: cellular and molecular mechanisms. These studies are designed to elucidate the molecular basis for the developmental and sex dependent regulation of hepatic P450 genes. Current research projects investigate: (a) the molecular mechanisms by which the ultraradian pattern of growth hormone secretion can either masculinize hepatic enzyme expression (pulsatile pituitary growth hormone secretion) or feminize enzyme expression (continuous growth hormone secretion); (b) the role of the plasma membrane growth hormone receptor in growth hormone signaling and its activation of STAT proteins, signal transducers and activators of transcription which undergo tyrosine phosphorylation followed by nuclear translocation in response to growth hormone pulses; (c) thyroid hormone regulation of NADPH P450 reductase at the transcriptional and post-transitional levels; and (d) regulation of liver gene expression by PPAR and other orphan receptors that belong to the steroid receptor gene superfamily and respond to structurally diverse drugs and environmental chemicals.
Molecular pharmacology of P450 enzymes and their roles in anti-cancer drug and foreign chemical metabolism. Current research projects in the area of P450 pharmacology and toxicology include the following: (a) development of improved strategies for cancer therapy using P450 genes to sensitize tumor cells to cancer chemotherapeutic prodrugs (P450-based cancer gene therapy); (b) role of cytochrome P450 in the bioactivation of clinically useful anti-cancer drugs, with an emphasis on enzymes expressed in human liver; and (c) therapeutic and toxicological consequences of the modulation of P450 enzyme profiles in response to foreign chemical exposure.
Doloff JC, Waxman DJ (2012). VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression. Cancer Res. 2012 Mar 1;72(5):1103-15. Epub 2012 Jan 11. Click here for pdf.
Zhang Y, Laz EV, Waxman DJ (2012). Dynamic, Sex-Differential STAT5 and BCL6 Binding to Sex-Biased, Growth Hormone-Regulated Genes in Adult Mouse Liver .Mol Cell Biol. 2012 Feb;32(4):880-96. Epub 2011 Dec 12. Click here for pdf.
Zhang Y, Klein K, Sugathan A, Nassery N, Dombkowski A, Zanger UM, Waxman DJ (2011). Transcriptional profiling of human liver identifies sex-biased genes associated with polygenic dyslipidemia and coronary artery disease. PLoS One. 2011;6(8):e23506. Epub 2011 Aug 12 Click here for pdf.
Doloff JC, Waxman DJ. Dual E1A oncolytic adenovirus: targeting tumor heterogeneity with two independent cancer-specific promoter elements, DF3/MUC1 and hTERT. (2011) Cancer Gene Ther Mar;18(3):153-66 . Click here for pdf.
Liu H, Tian N, Arany I, Bigler SA, Waxman DJ, Shah SV, Baliga R. Cytochrome P450 2B1 mediates complement-dependent sublytic injury in a model of membranous nephropathy..( 2010) J Biol Chem. Dec 24;285(52):40901-10. Click here for pdf.
Ling G, Sugathan A, Mazor T, Fraenkel E, Waxman DJ. Unbiased, genome-wide in vivo mapping of transcriptional regulatory elements reveals sex differences in chromatins structure associated with sex-specific liver gene expression. (2010) Molec Cell Biol 30, 5531-5544. Click here for PDF.
Doloff JC, Su T, Waxman DJ . Adenoviral delivery of pan-caspase inhibitor p35 enhaces bystander killing by P450 gene-directed enzyme prodrug theray using cyclophosphamide. (2010) BMC Cancer 10, 1-11. Click here for PDF.
Swanson HI, Njar VCO, Yu Z, Castro DJ, Gonzalez FJ, Williams DE, Huang Y, Kong ANT, Doloff JC, Ma J, Waxman, DJ. Symposium article targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy. (2010) Drug Metab Dispos 38, 539-544. Click here for PDF.
Wauthier V, Sugathan A, Meyer RD, Dombkowski AA, Waxman DJ. Intrinsic sex differences in the early growth hormone responsiveness of sex-secific genes in mouse liver (2010) Mol Endocrinol 24,667-678. Click here for PDF.
Ma J, Waxman DJ. Dominant effect of anti-angiogenesis in combination therapy involving cyclophosphamide and the VEGF receptor tyrosine kinase inhibitor axitinib. (2009) Clin Canc Res 15, 578-588. Click here for PDF.
Chin M, Herscovitch M, Zhang N, Waxman DJ, Gilmore TD. Overexpression of an activated REL mutant enhances the transformed state of the human B-lymphoma BJAB cell line and alters its gene expression profile. (2009) Oncogene 28, 2100-2111. Click here for PDF.
Lofgren S, Baldwin RM, Carleros M, Terelius Y, Fransson-Steen R, Mwinyi J, Waxman DJ, Ingelman-Sundberg M. Regulation of human CYP2C18 and CYP2C19 in transgenic mice: influence of castration, testosterone and growth hormone. (2009) Drug Metab Dispos 37, 1505-1512. Click here for PDF.
Meyer RD, Laz EV, Su T, Waxman DJ. Male-specific expression of hepatic Bcl6. Growth hormone-induced block of transcription elongation in females and binding to target genes inversely coordinated with STAT5. (2009) Molec Endocrinol, 23, 1914-1926. Click here for PDF.
Ma J, Waxman DJ. Collaboration between hepatic and intratumoral prodrug activation in a P450 prodrug-activation gene therapy model for cancer treatment. (2007) Molec Cancer Ther 6, 2879-2890. Click here for PDF.
Johnston TP, Waxman DJ. Circulating free fatty acids are increased independent of PPARg activity after administration of poloxamer 407 to mice. (2008) Can J Physiol Pharmacol 86, 643-649. Click here for PDF.
Doloff JC, Waxman DJ, Jounaidi Y. Human telomerase reverse transcriptase promoter-driven oncolytic adenovirus with E1B-19 kDa and E1B-55 kDa gene deletions. (2008) Human Gene Therapy 19, 1383-1399. Click here for PDF.
Ma J, Waxman DJ. 2007. Collaboration between hepatic and intratumoral prodrug activation in a P450 prodrug-activation gene therapy model for cancer treatment. Mol Cancer Ther. 2007 Nov;6(11):2879-90. Click here for PDF.
Chen CS, Jounaidi Y, Su T, Waxman DJ. 2007. Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model. Cancer Gene Ther. 2007 Dec;14(12):935-44. Click here for PDF
Clodfelter KH, Miles GD, Wauthier V, Holloway MG, Zhang X, Hodor P, Ray WJ, Waxman DJ. 2007. Role of STAT5a in regulation of sex-specific gene expression in female but not male mouse liver revealed by microarray analysis. Physiol Genomics. 2007 Sep 19;31(1):63-74. Click here for PDF
Ma X, Idle JR, Malfatti MA, Krausz KW, Nebert DW, Chen CS, Felton JS, Waxman DJ, Gonzalez FJ. 2007. Mouse lung CYP1A1 catalyzes the metabolic activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis 28, 732-737. Click here for PDF
Holloway MG, Cui Y, Laz EV, Hosui A, Hennighausen L, Waxman DJ. 2007. Loss of sexually dimorphic liver gene expression upon hepatocyte-specific deletion of Stat5a-Stat5b locus. Endocrinology 148, 1977-1986. Click here for PDF
Laz EV, Holloway MG, Chen CS, Waxman DJ.2007. Characterization of three growth hormone-responsive transcription factors preferentially expressed in adult female liver. Endocrinology. 2007 Jul;148(7):3327-37. Click here for PDF.
Gu J, Chen CS, Wei Y, Fang C, Xie F, Kannan K, Yang W, Waxman DJ, Ding X. 2007. A mouse model with liver-specific deletion and global suppression of the NADPH-cytochrome P450 reductase gene: characterization and utility for in vivo studies of cyclophosphamide disposition. J Pharm Exp Therap 321, 9-17. . Click here for PDF.
Sun L, Chen CS, Waxman DJ, Liu H, Halpert JR, Kumar S. 2007. Re-engineering cytochrome P450 2B11dH for enhanced metabolism of several substrates including the anti-cancer prodrugs cyclophosphamide and ifosfamide. Arch Biochem Biophys 458, 167-174. Click here for PDF.Jounaidi Y, Doloff JC, Waxman DJ. 2007. Conditionally replicating adenoviruses for cancer treatment. Curr Canc Drug Targets 7, 285-301. Click here for PDF
Clodfelter KH, Waxman DJ, Vajda S. 2006. Computational solvent mapping reveals the importance of local conformational changes for broad substrate specificity in mammalian cytochromes P450. Biochemistry. 45: 9393-9407. Click here for PDF.
Chang TK, Waxman DJ. 2006. Synthetic drugs and natural products as modulators of constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Drug Metab Rev. 38: 51-73. Review. Click here for PDF.
Gunther M, Waxman DJ, Wagner E, Ogris M. 2006. Effects of hypoxia and limited diffusion in tumor cell microenvironment on bystander effect of P450 prodrug therapy. Cancer Gene Ther. 13: 771-779. Click here for PDF.
Clodfelter KH, Holloway MG, Hodor P, Park SH, Ray WJ, Waxman DJ. Sex-dependent liver gene expression is extensive and largely dependent upon signal transducer and activator of transcription 5b (STAT5b): STAT5b-dependent activation of male genes and repression of female genes revealed by microarray analysis. 2006. Mol Endocrinol. 20: 1333-1351. Click here for PDF.
Shipley JM, Waxman DJ. Aryl hydrocarbon receptor-independent activation of estrogen receptor-dependent transcription by 3-methylcholanthrene. 2006. Toxicol Appl Pharmacol. 213: 87-97. Click here for PDF.
Cheung C, Yu A-M, Chen CS, Krausz KW, Byrd L, Feigenbaum L, Edwards RJ, Waxman DJ, Gonzalez FJ. 2006. Growth hormone determines sexual dimorphism of human P450 3A4 expression in transgenic mice. J Pharmacol Exp Ther, 316, 1328-1344. Click here for PDF.
Jounaidi Y, Chen CS, Veal GJ, Waxman DJ. 2006. Enhanced anti-tumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11. Molec Cancer Therapy, Mar;5(3):541-55. Click here for PDF.
Kumar S, Chen CS, Waxman DJ, Halpert JR. 2005. Directed evolution of mammalian cytochrome P450 2B1: mutations outside of the active site enhance the metabolism of several substrates including the anticancer prodrugs cyclophosphamide and ifosfamide. J Biol Chem 280, 19569-19575. Click here for PDF.
Riddick DS, Lee C, Ramji S, Chinje EC, Cowen RL, Williams KJ, Patterson AV, Stratford IJ, Morrow CS, Townsend AJ, Jounaidi Y, Chen CS, Su T, Lu H, Schwartz PS, Waxman DJ. 2005. Cancer chemotherapy and drug metabolism (Review). Drug Metab Dispos 33, 1083-1096. Click here for PDF.
Chen CS, Jounaidi Y, Waxman DJ. 2005. Enantioselective metabolism and cytotoxicity of R-ifosfamide and S-ifosfamide by tumor cell-expressed cytochromes P450. Drug Metab Dispos, 33, 1261-1267. Click here for PDF.
Waxman DJ, Chang TKH. 2005. Hormonal regulation of liver cytochrome P450 enzymes. In: Ortiz de Montellano PR, ed. Cytochrome P450: Structure, Mechanism and Biochemistry (Third Edition), Kluwer Academic/Plenum Publishers, NY, Chapter 9, 347-376. Click here for PDF.
Chang TKH, Waxman DJ. 2005. Pregnane X receptor-mediated transcription. Methods Enzymol 400 , 588-598. Click here for PDF.
Schlezinger JJ, Howard GJ, Hurst CH, Emberley JK, Waxman DJ, Webster T, Sherr DH. 2004. Environmental and endogenous PPARg agonists induce bone marrow B cell growth arrest and apoptosis: interactions between mono-(2-ethylhexyl) phthalate, 9- cis -retinoic acid, and 15-deoxy- D 12,14 -prostaglandin J2 J Immunol 173, 3165-3177. Click here for PDF.
Ahluwalia A, Clodfelter KH, Waxman DJ. 2004. Sexual dimorphism of rat liver gene expression: regulatory role of growth hormone revealed by DNA microarray analysis. Molec Endocrinol 18, 747-760. Click here for PDF.
Su T, Waxman DJ. 2004. Impact of dimethyl sulphoxide on expression of nuclear receptors and drug-inducible cytochromes P450 in primary rat hepatocytes. Arch Biochem Biophys 424, 226-234. Click here for PDF.
Chen CS, Lin JT, Goss KA, He Y, Halpert JR, Waxman DJ. 2004. Activation of the anti-cancer prodrugs cyclophosphamide and ifosfamide. Identification of P450 2B enzymes and site-specific mutants with improved enzyme kinetics. Molec Pharmacol 65, 1278-1285. Click here for PDF.
Shipley JM, Hurst CH, Tanaka SS, DeRoos FL, Butenhoff JL, Seacat AM, Waxman DJ. 2004. Trans-activation of PPARa and induction of PPARa target genes by perfluorooctane-based chemicals. Toxicol Sci 80, 151-160. Click here for PDF.
Jounaidi Y, Waxman DJ. 2004. Use of replication-conditional adenovirus as a helper system to enhance delivery of P450 prodrug-activation genes for cancer therapy. Cancer Res. Jan 1; 64(1):292-303. Click here for PDF.
Waxman DJ, Celenza JL. 2003. Sexual dimorphism of hepatic gene expression: novel biological role of KRAB zinc finger repressors revealed. Genes Dev. Nov 1; 17(21):2607-13. Click here for PDF.
Schwartz PS, Chen CS, Waxman DJ. 2003. Sustained P450 expression and prodrug activation in bolus cyclophosphamide-treated cultured tumor cells. Impact of prodrug schedule on P450 gene-directed enzyme prodrug therapy. Cancer Gene Therapy 10: 571-582. Click here for PDF.
Tannenbaum GS, Choi HK, Gurd W, Waxman DJ. 2001. Temporal relationship between the sexually dimorphic spontaneous GH secretory profiles and hepatic stat5 activity. Endocrinology 142: 4599-4606. Click here for PDF.
Park SH, Waxman DJ. 2001. Inhibitory cross-talk between STAT5b and liver nuclear factor HNF3beta. Impact on the regulation of growth hormone pulse-stimulated, male-specific liver cytochrome P450 gene expression. J Biol Chem. 276 43031-43039. Click here for PDF.
Huang Z, Waxman DJ. 2001. Modulation of cyclophosphamide-based cytochrome P450 gene therapy using liver P450 inhibitors. Cancer Gene Ther 8: 450-8. Click here for PDF.
Jounaidi Y, Waxman DJ. 2001. Frequent, moderate-dose cyclophosphamide administration improves the efficacy of cytochrome P-450/cytochrome P-450 reductase-based cancer gene therapy. Cancer Res 61: 4437-44. Click here for PDF.
Yu LJ, Matias J, Scudiero DA, Hite KM, Monks A, Sausville EA, Waxman DJ. 2001. P450 enzyme expression patterns in the NCI human tumor cell line panel. Drug Metab Dispos 29, 304-312. Click here for PDF.
Xie W, Radominska-Pandya A, Shi Y, Simon CM, Nelson MC, Ong ES, Waxman DJ, Evans RM. 2001. An essential role for SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci USA 98, 3375-3380. Click here for PDF.
Dillon JS, Yaney GC, Zhou Y, Voilley N, Bowen S, Chipkin S, Bliss CR, Schultz V, Schuit FC, Prentki M, Waxman DJ, Corkey BE. 2000. Dehydroepiandrosterone sulfate and beta-cell function: enhanced glucose-induced insulin secretion and altered gene expression in rodent pancreatic beta-cells. Diabetes Dec; 49(12):2012-20. Click here for PDF.
Choi HK, Waxman DJ. 2000. Related Articles Pulsatility of growth hormone (GH) signalling in liver cells: role of the JAK-STAT5b pathway in GH action. Growth Horm IGF Res Apr; 10 Suppl B:S1-8. Click here for PDF.
Choi HK, Waxman DJ. 2000. Related Articles Plasma growth hormone pulse activation of hepatic JAK-STAT5 signaling: developmental regulation and role in male-specific liver gene expression. Endocrinology Sep; 141(9):3245-55. Click here for PDF.
Delesque-Touchard N, Park SH, Waxman DJ .2000. Related Articles Synergistic action of hepatocyte nuclear factors 3 and 6 on CYP2C12 gene expression and suppression by growth hormone-activated STAT5b. PROPOSED MODEL FOR FEMALE-SPECIFIC EXPRESSION OF CYP2C12 IN ADULT RAT LIVER. J Biol Chem Nov 3;275(44):34173-82. Click here for PDF.
Huang Z, Raychowdhury MK, Waxman DJ. 2000. Impact of liver P450 reductase suppression on cyclophosphamide activation, pharmacokinetics and antitumoral activity in a cytochrome P450-based cancer gene therapy model. Cancer Gene Ther. 7: 1034-1042. Click here PDF.
Huang Z, Roy P, Waxman DJ. 2000. Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol. 59: 961-972. Click here for PDF.
Jounaidi Y, Waxman DJ. 2000. Combination of the bioreductive drug tirapazamine with the chemotherapeutic prodrug cyclophosphamide for P450/P450-reductase-based cancer gene therapy. Cancer Res. 60: 3761-3769. Click here for PDF.
Waxman DJ. 2000. Growth hormone pulse-activated STAT5 signalling: a unique regulatory mechanism governing sexual dimorphism of liver gene expression. Novartis Found Symp. 227: 61-81. Review. Click here for PDF.
Davey HW, Park SH, Grattan DR, McLachlan MJ, and Waxman DJ. 1999. STAT5b-deficient Mice Are Growth Hormone Pulse-resistant Role of STAT5b in Sex-Specific Liver P450 Expression. J Biol Chem 274: 35331-36. Click here for PDF.
Gebert CA, Park SH, and Waxman DJ. 1999. Down-regulation of liver JAK2-STAT5b signaling by the female plasma pattern of continuous growth hormone stimulation. Mol Endocrinol 13: 213-227. Click here for PDF.
Gebert CA, Park SH, and Waxman, DJ. 1999. Termination of growth hormone pulse-induced STAT5b signaling. Mol Endocrinol 13, 38-56. Click here for PDF.
Huang Z and Waxman DJ. 1999. High-performance liquid chromatographic-fluorescent method to determine chloroacetaldehyde, a neurotoxic metabolite of the anticancer drug ifosfamide, in plasma and in liver microsomal incubations. Anal Biochem 273:117-25. Click here for PDF.
Park SH, Liu X, Hennighausen L, Davey HW, and Waxman DJ. 1999. Distinctive roles of STAT5a and STAT5b in sexual dimorphism of hepatic P450 gene expression. Impact of Stat5a gene disruption. J Biol Chem 274: 7421-7430. Click here for PDF.
Roy P, Tretyakov O, Wright J, and Waxman DJ. 1999. Stereoselective metabolism of ifosfamide by human P-450s 3A4 and 2B6. Favorable metabolic properties of R-enantiomer. Drug Metab Dispos 27:1309-18. Click here for PDF.
Roy P, Yu LJ, Crespi CL, and Waxman DJ. 1999. Development of a substrate-activity based approach To identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 27: 655-66. Click here for PDF.
Waxman DJ, Chen L, Hecht JE, and Jounaidi Y. 1999. Cytochrome P450-based cancer gene therapy: recent advances and future prospects. Drug Metab Rev 31: 503-22. Click here for PDF.
Yu LJ, Drewes P, Gustafsson K, Brain EG, Hecht JE, and Waxman DJ. 1999. In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism: impact on pharmacokinetics and antitumor activity. J Pharmacol Exp Ther 288: 928-937. Click here for PDF.
Zhou YC and Waxman, DJ. 1999. STAT5b down-regulates peroxisome proliferator-activated receptor alpha transcription by inhibition of ligand-independent activation function region-1 trans-activation domain. J Biol Chem 274:29874-82. Click here for PDF.