The Cytochrome P450 2C8*3 Variant (rs11572080) Is Associated with Improved Asthma Symptom Control in Children and Altered Lipid Mediator Production and Inflammatory Response in Human Bronchial Epithelial Cells.

Autor:	Almestica-Roberts M; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Nguyen ND; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Sun L; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Serna SN; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Rapp E; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Burrell-Gerbers KL; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Memon TA; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Stone BL; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Nkoy FL; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Lamb JG; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Deering-Rice CE; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Rower JE; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah., Reilly CA; Department of Pharmacology and Toxicology, Center for Human Toxicology (M.A.-R., N.D.N., L.S., S.N.S., E.R., K.L.B.-G., T.A.M., J.G.L., C.E.D.-R., J.E.R., C.A.R.) and Department of Pediatrics, School of Medicine (B.L.S., F.L.N.), University of Utah, Salt Lake City, Utah chris.reilly@pharm.utah.edu.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2024 Jul 16; Vol. 52 (8), pp. 836-846. Date of Electronic Publication: 2024 Jul 16.
DOI:	10.1124/dmd.124.001684
Abstrakt:	This study investigated an association between the cytochrome P450 (CYP) 2C8*3 polymorphism with asthma symptom control in children and changes in lipid metabolism and pro-inflammatory signaling by human bronchial epithelial cells (HBECs) treated with cigarette smoke condensate (CSC). CYP genes are inherently variable in sequence, and while such variations are known to produce clinically relevant effects on drug pharmacokinetics and pharmacodynamics, the effects on endogenous substrate metabolism and associated physiologic processes are less understood. In this study, CYP2C8*3 was associated with improved asthma symptom control among children: Mean asthma control scores were 3.68 ( n = 207) for patients with one or more copies of the CYP2C8*3 allele versus 4.42 ( n = 965) for CYP2C8*1/*1 ( P = 0.0133). In vitro, CYP2C8*3 was associated with an increase in montelukast 36-hydroxylation and a decrease in linoleic acid metabolism despite lower mRNA and protein expression. Additionally, CYP2C8*3 was associated with reduced mRNA expression of interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL-8) by HBECs in response to CSC, which was replicated using the soluble epoxide hydrolase inhibitor, 12-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]-dodecanoic acid. Interestingly, 9(10)- and 12(13)- dihydroxyoctadecenoic acid, the hydrolyzed metabolites of 9(10)- and 12(13)- epoxyoctadecenoic acid, increased the expression of IL-6 and CXCL-8 mRNA by HBECs. This study reveals previously undocumented effects of the CYP2C8*3 variant on the response of HBECs to exogenous stimuli. SIGNIFICANCE STATEMENT: These findings suggest a role for CYP2C8 in regulating the epoxyoctadecenoic acid:dihydroxyoctadecenoic acid ratio leading to a change in cellular inflammatory responses elicited by environmental stimuli that exacerbate asthma. (Copyright © 2024 by The Author(s).)
Databáze:	MEDLINE
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