Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants
Metabolic-dysfunction-associated steatotic liver disease (MASLD), which affects 30 million people in the US and is anticipated to reach over 100 million by 2030, places a significant financial strain on the healthcare system. There is presently no FDA-approved treatment for MASLD despite its public...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/17/13406 |
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| author | Lanuza A. P. Faccioli Zeliha Cetin Zehra N. Kocas-Kilicarslan Kimberly Ortiz Yiyue Sun Zhiping Hu Takeshi Kurihara Edgar N. Tafaleng Rodrigo M. Florentino Zi Wang Mengying Xia Mark T. Miedel D. Lansing Taylor Jaideep Behari Alina Ostrowska Robert Constantine Albert Li Alejandro Soto-Gutierrez |
| author_facet | Lanuza A. P. Faccioli Zeliha Cetin Zehra N. Kocas-Kilicarslan Kimberly Ortiz Yiyue Sun Zhiping Hu Takeshi Kurihara Edgar N. Tafaleng Rodrigo M. Florentino Zi Wang Mengying Xia Mark T. Miedel D. Lansing Taylor Jaideep Behari Alina Ostrowska Robert Constantine Albert Li Alejandro Soto-Gutierrez |
| author_sort | Lanuza A. P. Faccioli |
| collection | DOAJ |
| description | Metabolic-dysfunction-associated steatotic liver disease (MASLD), which affects 30 million people in the US and is anticipated to reach over 100 million by 2030, places a significant financial strain on the healthcare system. There is presently no FDA-approved treatment for MASLD despite its public health significance and financial burden. Understanding the connection between point mutations, liver enzymes, and MASLD is important for comprehending drug toxicity in healthy or diseased individuals. Multiple genetic variations have been linked to MASLD susceptibility through genome-wide association studies (GWAS), either increasing MASLD risk or protecting against it, such as <i>PNPLA3</i> rs738409, <i>MBOAT7</i> rs641738, <i>GCKR</i> rs780094, <i>HSD17B13</i> rs72613567, and <i>MTARC1</i> rs2642438. As the impact of genetic variants on the levels of drug-metabolizing cytochrome P450 (CYP) enzymes in human hepatocytes has not been thoroughly investigated, this study aims to describe the analysis of metabolic functions for selected phase I and phase II liver enzymes in human hepatocytes. For this purpose, fresh isolated primary hepatocytes were obtained from healthy liver donors (n = 126), and liquid chromatography–mass spectrometry (LC–MS) was performed. For the cohorts, participants were classified into minor homozygotes and nonminor homozygotes (major homozygotes + heterozygotes) for five gene polymorphisms. For phase I liver enzymes, we found a significant difference in the activity of CYP1A2 in human hepatocytes carrying <i>MBOAT7</i> (<i>p =</i> 0.011) and of CYP2C8 in human hepatocytes carrying <i>PNPLA3</i> (<i>p</i> = 0.004). It was also observed that the activity of CYP2C9 was significantly lower in human hepatocytes carrying <i>HSD17B13</i> (<i>p</i> = 0.001) minor homozygous compared to nonminor homozygous. No significant difference in activity of CYP2E1, CYP2C8, CYP2D6, CYP2E1, CYP3A4, ECOD, FMO, MAO, AO, and CES2 and in any of the phase II liver enzymes between human hepatocytes carrying genetic variants for <i>PNPLA3</i> rs738409, <i>MBOAT7</i> rs641738, GCKR rs780094, <i>HSD17B13</i> rs72613567, and <i>MTARC1</i> rs2642438 were observed. These findings offer a preliminary assessment of the influence of genetic variations on drug-metabolizing cytochrome P450 (CYP) enzymes in healthy human hepatocytes, which may be useful for future drug discovery investigations. |
| first_indexed | 2024-03-10T23:21:33Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:21:33Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8471cbb831af478fb2c14395e536252e2023-11-19T08:16:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124171340610.3390/ijms241713406Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic VariantsLanuza A. P. Faccioli0Zeliha Cetin1Zehra N. Kocas-Kilicarslan2Kimberly Ortiz3Yiyue Sun4Zhiping Hu5Takeshi Kurihara6Edgar N. Tafaleng7Rodrigo M. Florentino8Zi Wang9Mengying Xia10Mark T. Miedel11D. Lansing Taylor12Jaideep Behari13Alina Ostrowska14Robert Constantine15Albert Li16Alejandro Soto-Gutierrez17Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADepartment of Statistics, University of Pittsburgh, Pittsburgh, PA 15213, USADrug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USADrug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USAPittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, PA 15261, USAPittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, PA 15261, USADepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USADiscovery Life Sciences, Huntsville, AL 35806, USADiscovery Life Sciences, Huntsville, AL 35806, USADepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USAMetabolic-dysfunction-associated steatotic liver disease (MASLD), which affects 30 million people in the US and is anticipated to reach over 100 million by 2030, places a significant financial strain on the healthcare system. There is presently no FDA-approved treatment for MASLD despite its public health significance and financial burden. Understanding the connection between point mutations, liver enzymes, and MASLD is important for comprehending drug toxicity in healthy or diseased individuals. Multiple genetic variations have been linked to MASLD susceptibility through genome-wide association studies (GWAS), either increasing MASLD risk or protecting against it, such as <i>PNPLA3</i> rs738409, <i>MBOAT7</i> rs641738, <i>GCKR</i> rs780094, <i>HSD17B13</i> rs72613567, and <i>MTARC1</i> rs2642438. As the impact of genetic variants on the levels of drug-metabolizing cytochrome P450 (CYP) enzymes in human hepatocytes has not been thoroughly investigated, this study aims to describe the analysis of metabolic functions for selected phase I and phase II liver enzymes in human hepatocytes. For this purpose, fresh isolated primary hepatocytes were obtained from healthy liver donors (n = 126), and liquid chromatography–mass spectrometry (LC–MS) was performed. For the cohorts, participants were classified into minor homozygotes and nonminor homozygotes (major homozygotes + heterozygotes) for five gene polymorphisms. For phase I liver enzymes, we found a significant difference in the activity of CYP1A2 in human hepatocytes carrying <i>MBOAT7</i> (<i>p =</i> 0.011) and of CYP2C8 in human hepatocytes carrying <i>PNPLA3</i> (<i>p</i> = 0.004). It was also observed that the activity of CYP2C9 was significantly lower in human hepatocytes carrying <i>HSD17B13</i> (<i>p</i> = 0.001) minor homozygous compared to nonminor homozygous. No significant difference in activity of CYP2E1, CYP2C8, CYP2D6, CYP2E1, CYP3A4, ECOD, FMO, MAO, AO, and CES2 and in any of the phase II liver enzymes between human hepatocytes carrying genetic variants for <i>PNPLA3</i> rs738409, <i>MBOAT7</i> rs641738, GCKR rs780094, <i>HSD17B13</i> rs72613567, and <i>MTARC1</i> rs2642438 were observed. These findings offer a preliminary assessment of the influence of genetic variations on drug-metabolizing cytochrome P450 (CYP) enzymes in healthy human hepatocytes, which may be useful for future drug discovery investigations.https://www.mdpi.com/1422-0067/24/17/13406metabolic-dysfunction-associated steatotic liver diseasemetabolic dysfunction-associated steatohepatitisnonalcoholic steatohepatitisend-stage liver diseasegenetic polymorphisms |
| spellingShingle | Lanuza A. P. Faccioli Zeliha Cetin Zehra N. Kocas-Kilicarslan Kimberly Ortiz Yiyue Sun Zhiping Hu Takeshi Kurihara Edgar N. Tafaleng Rodrigo M. Florentino Zi Wang Mengying Xia Mark T. Miedel D. Lansing Taylor Jaideep Behari Alina Ostrowska Robert Constantine Albert Li Alejandro Soto-Gutierrez Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants International Journal of Molecular Sciences metabolic-dysfunction-associated steatotic liver disease metabolic dysfunction-associated steatohepatitis nonalcoholic steatohepatitis end-stage liver disease genetic polymorphisms |
| title | Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants |
| title_full | Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants |
| title_fullStr | Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants |
| title_full_unstemmed | Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants |
| title_short | Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants |
| title_sort | evaluation of human hepatocyte drug metabolism carrying high risk or protection associated liver disease genetic variants |
| topic | metabolic-dysfunction-associated steatotic liver disease metabolic dysfunction-associated steatohepatitis nonalcoholic steatohepatitis end-stage liver disease genetic polymorphisms |
| url | https://www.mdpi.com/1422-0067/24/17/13406 |
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