Background This study aimed to systematically profile the alterations and sex- and age-related differences in the drug metabolizing enzymes (DMEs) in a KRAS-mutant mouse model of lung cancer (KRAS mice). Methodology In this study, the LC-MS/MS approach and a probe substrate method were used to detect the alterations in 21 isoforms of DMEs, as well as the enzymatic activities of five isoforms, respectively. Western blotting was applied to study the protein expression of four related receptors. Results The proteins contents of CYP2C29 and CYP3A11, were significantly downregulated in the livers of male KRAS mice at 26 weeks (3.7- and 4.4-fold, respectively, p < 0.05). SULT1A1 and SULT1D1 were upregulated by 1.8- to 7.0- fold at 20 (p = 0.015 and 0.017, respectively) and 26 weeks (p = 0.055 and 0.031, respectively). There were positive correlations between protein expression and enzyme activity for CYP2E1, UGT1A9, SULT1A1 and SULT1D1 (r2 ≥ 0.5, p < 0.001). Western blotting analysis revealed the downregulation of AHR, FXR and PPARα protein expression in male KRAS mice at 26 weeks. For sex-related differences, CYP2E1 was male-predominant and UGT1A2 was female-predominant in the kidney. UGT1A1 and UGT1A5 expression was female-predominant, whereas UGT2B1 exhibited male-predominant expression in liver tissue. For the tissue distribution of DMEs, 21 subtypes of DMEs were all expressed in liver tissue. In the intestine, the expression levels of CYP2C29, CYP27A1, UGT1A2, 1A5, 1A6a, 1A9, 2B1, 2B5 and 2B36 were under the limitation of quantification. The subtypes of CYP7A1, 1B1, 2E1 and UGT1A1, 2A3, 2B34 were detected in kidney tissue. Conclusions This study, for the first time, unveils the variations and sex- and age-related differences in DMEs in C57 BL/6 (WT) mice and KRAS mice.

中文翻译：

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KRAS突变肺癌小鼠模型中药物代谢酶表达的变化及性别和年龄相关差异

背景 本研究旨在系统地分析 KRAS 突变肺癌小鼠模型（KRAS 小鼠）中药物代谢酶 (DME) 的改变以及与性别和年龄相关的差异。方法 在本研究中，LC-MS/MS 方法和探针底物法分别用于检测 21 种 DME 异构体的变化以及 5 种异构体的酶活性。Western印迹用于研究四种相关受体的蛋白质表达。结果 26周时雄性KRAS小鼠肝脏中CYP2C29和CYP3A11蛋白含量显着下调（分别为3.7倍和4.4倍，p < 0.05）。SULT1A1 和 SULT1D1 在 20 周（分别为 p = 0.015 和 0.017）和 26 周（分别为 p = 0.055 和 0.031）上调 1.8 至 7.0 倍。CYP2E1、UGT1A9、SULT1A1 和 SULT1D1 的蛋白表达与酶活性呈正相关（r2 ≥ 0.5，p < 0.001）。Western印迹分析显示雄性KRAS小鼠在26周时AHR、FXR和PPARα蛋白表达下调。对于性别相关差异，CYP2E1 在肾脏中以男性为主，UGT1A2 以女性为主。UGT1A1 和 UGT1A5 表达以女性为主，而 UGT2B1 在肝组织中表现出男性为主的表达。对于DMEs的组织分布，21个DMEs亚型均在肝组织中表达。在肠道中，CYP2C29、CYP27A1、UGT1A2、1A5、1A6a、1A9、2B1、2B5和2B36的表达水平受到定量的限制。在肾组织中检测到CYP7A1、1B1、2E1和UGT1A1、2A3、2B34亚型。结论 本研究，