Variability in Expression of CYP3A5 in Human Fetal Liver.
| Autor: | Vyhlidal CA; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri (C.A.V., R.E.P., R.G., J.S.L.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (J.C.C., D.L.S., K.E.T.) cvyhlidal@cmh.edu., Pearce RE; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri (C.A.V., R.E.P., R.G., J.S.L.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (J.C.C., D.L.S., K.E.T.)., Gaedigk R; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri (C.A.V., R.E.P., R.G., J.S.L.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (J.C.C., D.L.S., K.E.T.)., Calamia JC; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri (C.A.V., R.E.P., R.G., J.S.L.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (J.C.C., D.L.S., K.E.T.)., Shuster DL; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri (C.A.V., R.E.P., R.G., J.S.L.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (J.C.C., D.L.S., K.E.T.)., Thummel KE; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri (C.A.V., R.E.P., R.G., J.S.L.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (J.C.C., D.L.S., K.E.T.)., Leeder JS; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri (C.A.V., R.E.P., R.G., J.S.L.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (J.C.C., D.L.S., K.E.T.). |
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| Jazyk: | angličtina |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2015 Aug; Vol. 43 (8), pp. 1286-93. Date of Electronic Publication: 2015 May 15. |
| DOI: | 10.1124/dmd.115.064998 |
| Abstrakt: | Members of the cytochrome P450 3A (CYP3A) subfamily of drug metabolizing enzymes exhibit developmental changes in expression in human liver characterized by a transition between CYP3A7 and CYP3A4 over the first few years of life. In contrast, the developmental expression of CYP3A5 is less well understood due to polymorphic expression of the enzyme in human tissues as a result of the prevalence of the CYP3A5*3 allele, which leads to alternative splicing. We further explored the expression of CYP3A5 and the impact of alternative splicing on the variability of CYP3A5 functional activity in a large bank of human prenatal liver samples (7 to 32 weeks of age postconception). The expression of normally spliced CYP3A5 mRNA in all human fetal liver samples varied 235-fold whereas CYP3A5 SV1 mRNA was only detected in fetal liver samples with at least one CYP3A5*3 allele. Formation of 1'-OH midazolam (MDZ) varied 79-fold, and the ratio of 1'-OH MDZ to 4-OH MDZ varied 8-fold and depended on the presence or absence of the CYP3A5*3 allele. Formation of 4-OH MDZ was significantly associated with 1'-OH MDZ (r(2) = 0.76, P < 0.0001) but varied (36-fold) independently of CYP3A5 genotype or expression. The substantial interindividual variability that remains even after stratification for CYP3A5 genotype suggests that factors such as environmental exposure and epigenetic alterations act in addition to genetic variation to contribute to the variability of CYP3A5 expression in human prenatal liver. (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.) |
| Databáze: | MEDLINE |
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