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4-Aminophenol (4-AP) and D-serine are established rodent nephrotoxins that selectively damage renal proximal tubules. In an attempt to understand the mechanism of action of these toxicants in greater detail, a high throughput proteomics approach was used to profile protein changes in the plasma of animals treated with these compounds. Male Fischer 344 and Alderley Park rats were treated with increasing doses of 4-AP or D-serine and plasma samples were collected over time. Control groups received either saline or the non-toxic enantiomer, L-serine. Using high throughput two-dimensional gel analysis, a number of plasma proteins showing dose- and time-dependent regulation were identified. One toxicity-associated plasma protein was identified as the cellular enzyme fumarylacetoacetate hydrolase (FAH), which is known to be required for tyrosine metabolism. The FAH gene is mutated in the human genetic disorder type I tyrosinaemia, which is associated with liver and kidney abnormalities and neurological disorders. FAH was elevated in the plasma of animals treated with 4-AP and D-serine at early time points and returned to baseline levels after 3 weeks. The protein was not elevated in the plasma of control animals or those treated with L-serine. The presence of FAH in plasma is intriguing as it is normally a cellular enzyme with no known function in plasma. It is possible that 4-AP and D-serine may work through a previously unknown mechanism in the kidney via regulation of tyrosine metabolism or FAH activity. Therefore, FAH may function in a fashion analogous to the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes that are used to measure liver injury. The link between kidney toxicants and inherited tyrosinaemia also raises the possibility that FAH may be a marker of kidney toxicity in humans. These observations highlight the value of proteomics in identifying new biomarkers and providing new unprecedented insights into complex biological mechanisms.

Original publication

DOI

10.1080/13547500412331332977

Type

Journal article

Journal

Biomarkers

Publication Date

05/2003

Volume

8

Pages

272 - 286

Keywords

Aminophenols, Animals, Biomarkers, Blood Proteins, Dose-Response Relationship, Drug, Electrophoresis, Gel, Two-Dimensional, Hydrolases, Kidney Diseases, Male, Proteomics, Rats, Rats, Inbred Strains, Serine, Toxins, Biological, Up-Regulation