The overall objective of this grant proposal is to identify the genetic and hormonal factors that define inter-individual differences in the expression of CYP3A in humans. We have directed our efforts to the study of CYP3A because of the central role that it has in the metabolic elimination of numerous drugs, including several with a narrow range of efficacious and nontoxic blood concentrations. We will test the hypothesis that """"""""The steady-state level of CYP3A4 in the human small intestine is controlled primarily by 1,25-dihydroxy vitamin D3 signaling through the vitamin D receptor and the CYP3A4 PXR response element,"""""""" with the following Specific Aims:
Aim 1. Determine in healthy adults whether intestinal CYP3A4 phenotype co-varies with CYP24 phenotype, a reporter for intestinal VDR-mediated transcriptional activation. We will also determine whether variability in intestinal CYP3A4 content is regulated by intestinal VDR mRNA content and plasma 1,25-D3 level.
Aim 2. Demonstrate that acute 1,25-D3 treatment increases intestinal CYP3A23 transcription in the rat, and that 1,25-D3 replacement therapy can induce CYP3A4 transcription activity in patients with end stage renal disease. We will also test the hypothesis that """"""""Inheritance of an A6981G mutation within intron-3 of the CYP3A5 gene controls the expression of hepatic and intestinal CYP3A5, and influence the oral bioavailability of some CYP3A drug substrates"""""""" with the following Specific Aims:
Aim 3. Characterize and compare the CYP3A4- and CYP3A5-dependent intrinsic metabolic clearance for 10 different drugs using a heterologous expression system and CYP3A-phenotyped human liver and intestinal microsomes. In addition, we will determine in healthy Caucasian and African-American adults whether the CYP3A5*1 genotype successfully predicts, on average, a higher midazolam clearances than that for subjects with the homozygous CYP3A5*3 genotype. We will also demonstrate that for African-Americans, there is a CYP3A5*1 gene-dose effect for the accumulation of properly spliced mRNA and CYP3A5 protein in duodenal biopsy tissue and for in vivo midazolam clearance.
Aim 4. Determine whether variability in the in vivo oral clearance of cyclosporine is determined, in part, by the CYP3A5 genotype. If the proposed hypotheses are validated, it may become possible to develop simple genotyping and phenotyping tests for individualizing therapy with narrow therapeutic index drugs, such as cyclosporine.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Okita, Richard T
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University of Washington
Schools of Pharmacy
United States
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Wong, Timothy; Wang, Zhican; Chapron, Brian D et al. (2018) Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D3-3-O-Sulfate, a Major Circulating Vitamin D Metabolite in Humans. Drug Metab Dispos 46:367-379
Hawkes, Colin Patrick; Li, Dong; Hakonarson, Hakon et al. (2017) CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients With CYP24A1 Mutations. J Clin Endocrinol Metab 102:1440-1446
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Fohner, Alison E; Wang, Zhican; Yracheta, Joseph et al. (2016) Genetics, Diet, and Season Are Associated with Serum 25-Hydroxycholecalciferol Concentration in a Yup'ik Study Population from Southwestern Alaska. J Nutr 146:318-25
Yamaura, Yoshiyuki; Chapron, Brian D; Wang, Zhican et al. (2016) Functional Comparison of Human Colonic Carcinoma Cell Lines and Primary Small Intestinal Epithelial Cells for Investigations of Intestinal Drug Permeability and First-Pass Metabolism. Drug Metab Dispos 44:329-35
de Boer, Ian H; Sachs, Michael C; Chonchol, Michel et al. (2014) Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials. Am J Kidney Dis 64:187-97
Wang, Zhican; Wong, Timothy; Hashizume, Takanori et al. (2014) Human UGT1A4 and UGT1A3 conjugate 25-hydroxyvitamin D3: metabolite structure, kinetics, inducibility, and interindividual variability. Endocrinology 155:2052-63
Poulton, Emma Jane; Levy, Lisa; Lampe, Johanna W et al. (2013) Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo. Toxicol Appl Pharmacol 266:122-31
Wang, Zhican; Schuetz, Erin G; Xu, Yang et al. (2013) Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. J Steroid Biochem Mol Biol 136:54-8

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