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.
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
Drug Metab Dispos. 2024 Jul 16;52(8):836-846. doi: 10.1124/dmd.124.001684.
This study investigated an association between the cytochrome P450 (CYP) 2C83 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, CYP2C83 was associated with improved asthma symptom control among children: Mean asthma control scores were 3.68 ( = 207) for patients with one or more copies of the CYP2C83 allele versus 4.42 ( = 965) for CYP2C81/1 ( = 0.0133). In vitro, CYP2C83 was associated with an increase in montelukast 36-hydroxylation and a decrease in linoleic acid metabolism despite lower mRNA and protein expression. Additionally, CYP2C83 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 CYP2C83 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.
这项研究调查了细胞色素 P450 (CYP) 2C83 多态性与儿童哮喘症状控制之间的关联，以及香烟烟雾冷凝物 (CSC) 处理的人支气管上皮细胞 (HBEC) 中脂质代谢和促炎信号的变化。CYP 基因在序列上固有地多变，虽然这种变化已知会对药物药代动力学和药效学产生临床相关影响，但对内源性底物代谢和相关生理过程的影响了解较少。在这项研究中，CYP2C83 与儿童哮喘症状控制的改善有关：携带一个或多个 CYP2C83 等位基因的患者平均哮喘控制评分为 3.68（=207），而 CYP2C81/1（=0.0133）的患者平均哮喘控制评分为 4.42（=965）。在体外，尽管 CYP2C83 的 mRNA 和蛋白表达较低，但与 montelukast 36-羟化作用增加和 linoleic 酸代谢减少有关。此外，CYP2C83 与 HBEC 对 CSC 反应时白细胞介素-6 (IL-6) 和 C-X-C 基序趋化因子配体 8 (CXCL-8) 的 mRNA 表达降低有关，这一结果使用可溶性环氧化物水解酶抑制剂 12-[[(三环[3.3.1.13,7]癸-1-基氨基)羰基]氨基]-十二烷酸得到了复制。有趣的是，9(10)-和 12(13)-二羟基十八碳烯酸，9(10)-和 12(13)-环氧十八碳烯酸的水解代谢物，增加了 HBEC 中白细胞介素-6 和 CXCL-8 mRNA 的表达。这项研究揭示了 CYP2C83 变体对 HBEC 对外源刺激反应的先前未记录的影响。意义声明：这些发现表明 CYP2C8 在调节环氧十八碳烯酸：二羟基十八碳烯酸比值中起作用，导致细胞炎症反应的变化，这些变化由环境刺激引发，加重哮喘。
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