B. P. Norman, H. Sutherland, P. J. M. Wilson, D. A. Rutland, A. M. Milan, A. T. Hughes, A. S. Davison, M. Khedr, J. C. Jarvis, J. A. Gallagher, G. Bou-Gharios, L. R. Ranganath
{"title":"碱蛋白尿小鼠模型的肝胆循环和同源戊二酸的主要尿排泄。","authors":"B. P. Norman, H. Sutherland, P. J. M. Wilson, D. A. Rutland, A. M. Milan, A. T. Hughes, A. S. Davison, M. Khedr, J. C. Jarvis, J. A. Gallagher, G. Bou-Gharios, L. R. Ranganath","doi":"10.1002/jimd.12728","DOIUrl":null,"url":null,"abstract":"<p>Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in bile in AKU (mean [±SD] = 1003[±410] μmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] μmol/L). Biliary tyrosine, 3(4-hydroxyphenyl)pyruvic acid (HPPA) and 3(4-hydroxyphenyl)lactic acid (HPLA) are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion. These data provide new insights into pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. We propose that our finding of approximately 3.8 times greater urinary HGA excretion in AKU mice compared with patients is one reason for the lack of extensive tissue ochronosis in the AKU mouse model.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 4","pages":"664-673"},"PeriodicalIF":4.2000,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12728","citationCount":"0","resultStr":"{\"title\":\"Hepatobiliary circulation and dominant urinary excretion of homogentisic acid in a mouse model of alkaptonuria\",\"authors\":\"B. P. Norman, H. Sutherland, P. J. M. Wilson, D. A. Rutland, A. M. Milan, A. T. Hughes, A. S. Davison, M. Khedr, J. C. Jarvis, J. A. Gallagher, G. Bou-Gharios, L. R. Ranganath\",\"doi\":\"10.1002/jimd.12728\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in bile in AKU (mean [±SD] = 1003[±410] μmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] μmol/L). Biliary tyrosine, 3(4-hydroxyphenyl)pyruvic acid (HPPA) and 3(4-hydroxyphenyl)lactic acid (HPLA) are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion. These data provide new insights into pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. We propose that our finding of approximately 3.8 times greater urinary HGA excretion in AKU mice compared with patients is one reason for the lack of extensive tissue ochronosis in the AKU mouse model.</p>\",\"PeriodicalId\":16281,\"journal\":{\"name\":\"Journal of Inherited Metabolic Disease\",\"volume\":\"47 4\",\"pages\":\"664-673\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-03-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12728\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Inherited Metabolic Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jimd.12728\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Inherited Metabolic Disease","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jimd.12728","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
摘要
苯丙氨酸-酪氨酸(phe-tyr)代谢过程中特定酶活性的改变会导致该途径中各种代谢物底物的不完全分解。苯丙氨酸-酪氨酸(phe-tyr)代谢途径代谢物高戊酸(HGA)的生物液体浓度和组织蓄积增加是遗传性疾病碱丙尿症(AKU)病理生理学的核心。尼替西酮是一种治疗 AKU 和遗传性酪氨酸血症 1 型的特许药物,可抑制产生 HGA 的酶。这项研究的目的是调查服用和停用尼替西酮的 AKU 小鼠主要生物流体和组织中的酪氨酸代谢物含量,以便对这些代谢状态改变时代谢物的生物分布有新的认识。数据首次显示,HGA 存在于 AKU 的胆汁中(平均值 [±SD] = 1003[±410] μmol/L;尼替西酮处理的 AKU 平均值 [±SD] = 45[±23] μmol/L)。服用尼替西酮后,胆汁中的酪氨酸、3(4-羟基苯基)丙酮酸(HPPA)和 3(4-羟基苯基)乳酸(HPLA)也会增加。尿液被证实是未经治疗的 AKU 中 HGA 的主要排泄途径,但也有胆汁排泄的迹象。这些数据为了解嗜铬酪氨酸代谢物的生物分布和代谢途径提供了新的视角,首次表明肝胆排泄也是该途径中代谢物总量的一部分。我们的数据表明,胆汁排出有机酸和其他代谢物可能在代谢紊乱中发挥着未被重视的作用。我们发现,AKU 小鼠尿液中 HGA 的排泄量是患者的约 3.8 倍,这也是 AKU 小鼠模型中没有大面积组织chronosis 的原因之一。
Hepatobiliary circulation and dominant urinary excretion of homogentisic acid in a mouse model of alkaptonuria
Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in bile in AKU (mean [±SD] = 1003[±410] μmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] μmol/L). Biliary tyrosine, 3(4-hydroxyphenyl)pyruvic acid (HPPA) and 3(4-hydroxyphenyl)lactic acid (HPLA) are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion. These data provide new insights into pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. We propose that our finding of approximately 3.8 times greater urinary HGA excretion in AKU mice compared with patients is one reason for the lack of extensive tissue ochronosis in the AKU mouse model.
期刊介绍:
The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).