Age-related changes in hepatic expression and activity of drug metabolizing enzymes in male wild-type and breast cancer resistance protein knockout mice
| Autor: | Xiaoxiao Qi, Sijing Zeng, Haojia Wang, Haihui Zheng, Linlin Lu, Xia Yang, Jia Yu, Zhongqiu Liu, Huangyu Jiang, Lijun Zhu, Xia Gong, Liping Wang, Ming Hu, Ying Wang, Jiamei Chen |
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| Rok vydání: | 2018 |
| Předmět: |
Male
medicine.medical_specialty Aging Abcg2 Pharmaceutical Science 030226 pharmacology & pharmacy 03 medical and health sciences 0302 clinical medicine Cytochrome P-450 Enzyme System Age related Internal medicine medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Pharmacology (medical) RNA Messenger Glucuronosyltransferase Pharmacology Mice Knockout biology Chemistry CYP1A2 Wild type Cytochrome P450 General Medicine CYP2E1 Drug metabolizing enzymes Endocrinology 030220 oncology & carcinogenesis Knockout mouse biology.protein Microsomes Liver |
| Zdroj: | Biopharmaceuticsdrug disposition. 39(7) |
| ISSN: | 1099-081X |
| Popis: | This study aimed to reveal age-related changes in the expression and activity of seven hepatic drug metabolizing enzymes (DMEs) in male wild-type and breast cancer resistance protein knockout (Bcrp1-/- ) FVB mice. The protein expression of four cytochrome P450 (Cyps) (Cyp3a11, 2d22, 2e1, and 1a2), and three UDP-glucuronosyltransferases (Ugts) (Ugt1a1, 1a6a, and 1a9) in liver microsomes of wild-type and Bcrp1-/- FVB mice at different ages were determined using a validated ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method. The activities and mRNA levels of these DMEs were measured using the probe substrates method and real-time PCR, respectively. In the liver of wild-type FVB mice, Cyp3a11, 2d22, 2e1, 1a2, Ugt1a1, and 1a6a displayed maximum protein levels at 6-9 weeks of age. Cyp1a2, Ugt1a1, 1a6a, and 1a9 showed maximum activities at 6-9 weeks of age, whereas Cyp3a11, 2d22, and 2e1 showed maximum activities in 1-3-week-old mice. Additionally, most of the DMEs showed maximum mRNA levels in 17-week-old mice liver. Compared with wild-type FVB mice, the protein levels of these DMEs showed no significant changes in Bcrp1-/- FVB mice liver. However, the activity of Cyp2e1 was increased and that of Cyp2d22 was decreased. In conclusion, the seven hepatic DMEs in FVB mice liver showed significant alterations in an isoform-specific manner with increased age. Although the protein levels of these DMEs showed no significant changes, the activities of Cyp2e1 and 2d22 were changed in Bcrp1-/- mice. |
| Databáze: | OpenAIRE |
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