A systems biology approach to understanding elevated serum alanine transaminase levels in a clinical trial with ximelagatran

被引：40

作者：

Andersson, Ulf ^{[1
]}

Lindberg, Johan ^{[1
]}

Wang, Shunghuang ^{[3
]}

Balasubramanian, Raji ^{[2
]}

Marcusson-Stahl, Maritha ^{[1
]}

Hannula, Mira ^{[1
]}

Zeng, Chenhui ^{[3
]}

Juhasz, Peter J. ^{[3
]}

Kolmert, Johan ^{[1
]}

Backstrom, Jonas ^{[1
]}

Nord, Lars ^{[1
]}

Nilsson, Kerstin ^{[4
]}

Martin, Steve ^{[3
]}

Glinghammar, Bjorn ^{[1
]}

Cederbrant, Karin ^{[1
]}

Schuppe-Koistinen, Ina ^{[1
]}

机构：

[1] AstraZeneca R&D, Safety Assessment, Mol Toxicol, SE-15185 Sodertalje, Sweden

[2] Univ Massachusetts, Shrewsbury, MA USA

[3] BG Med, Waltham, MA 02451 USA

[4] AstraZeneca R&D, Dis Biol, S-15185 Sodertalje, Sweden

来源：

BIOMARKERS | 2009年 / 14卷 / 08期

关键词：

Liver injury; systems biology; alanine aminotransferase; pyruvate; ximelagatran; GCN2 EIF2-ALPHA KINASE; STIMULATING FACTOR-I; PROTEIN-S; C4B-BINDING PROTEIN; PYRUVATE; DRUG; EXPRESSION; RECEPTOR; INJURY; LIVER;

D O I：

10.3109/13547500903261354

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Ximelagatran was developed for the prevention and treatment of thromboembolic conditions. However, in long-term clinical trials with ximelagatran, the liver injury marker, alanine aminotransferase (ALT) increased in some patients. Analysis of plasma samples from 134 patients was carried out using proteomic and metabolomic platforms, with the aim of finding predictive biomarkers to explain the ALT elevation. Analytes that were changed after ximelagatran treatment included 3-hydroxybutyrate, pyruvic acid, CSF1R, Gc-globulin, L-glutamine, protein S and alanine, etc. Two of these analytes (pyruvic acid and CSF1R) were studied further in human cell cultures in vitro with ximelagatran. A systems biology approach applied in this study proved to be successful in generating new hypotheses for an unknown mechanism of toxicity.

引用

页码：572 / 586

页数：15

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