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Disruption of NaS1 sulfate transport function in mice leads to enhanced acetaminophen‐induced hepatotoxicity
Author(s) -
Lee Soohyun,
Dawson Paul A.,
Hewavitharana Amitha K.,
Shaw P. Nicholas,
Markovich Daniel
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21207
Subject(s) - acetaminophen , detoxification (alternative medicine) , xenobiotic , transporter , chemistry , pharmacology , glutathione , drug metabolism , sulfate , glucuronide , metabolism , toxicity , biochemistry , enzyme , biology , medicine , gene , pathology , alternative medicine , organic chemistry
Sulfate is required for detoxification of xenobiotics such as acetaminophen (APAP), a leading cause of liver failure in humans. The NaS1 sulfate transporter maintains blood sulfate levels sufficiently high for sulfonation reactions to work effectively for drug detoxification. In the present study, we identified two loss‐of‐function polymorphisms in the human NaS1 gene and showed the Nas1‐null mouse to be hypersensitive to APAP hepatotoxicity. APAP treatment led to increased liver damage and decreased hepatic glutathione levels in the hyposulfatemic Nas1‐null mice compared with that in normosulfatemic wild‐type mice. Analysis of urinary APAP metabolites revealed a significantly lower ratio of APAP‐sulfate to APAP‐glucuronide in the Nas1‐null mice. These results suggest hyposulfatemia increases sensitivity to APAP‐induced hepatotoxicity by decreasing the sulfonation capacity to metabolize APAP. In conclusion , the results of this study highlight the importance of plasma sulfate level as a key modulator of acetaminophen metabolism and suggest that individuals with reduced NaS1 sulfate transporter function would be more sensitive to hepatotoxic agents. (H EPATOLOGY 2006;43: 1241–1247.)