Abstract
Bile acids represent a large class of steroid acids synthesized in the liver and further metabolized by many bacterial and mammalian enzymes. Variations in bile acid levels can be used as a measure of liver function. There still exists, however, a need to study the variation of individual circulating bile acids in the context of hepatotoxity or liver disease. Acetaminophen (APAP), a drug commonly taken to relieve pain and decrease fever, is known to cause acute liver failure at high doses. We have developed a targeted liquid chromatography-tandem mass spectrometry method to monitor the effects of different doses of APAP on the bile acid plasma profile in a rat model. The analysis method was optimized to ensure chromatographic resolution of isomeric species using a mixture of 46 standard bile acids, and 14 isotopically-labeled internal standard (IS) compounds detected in multiple reaction monitoring (MRM) mode on a triple quadrupole mass spectrometer. Four doses of acetaminophen were studied, the highest of which shows signs of hepatotoxicity in rats. This targeted method revealed that high dose APAP has an important effect on bile acid profiles. Changes were seen in several unconjugated bile acids as well as glycine conjugates; however, no obvious changes were apparent for taurine-conjugated species.
Highlights
Bile acids play many roles crucial for metabolism and liver health
A targeted liquid chromatography-multiple reaction monitoring (LC-MRM) method was developed to monitor 46 bile acids in rat plasma following a simple sample preparation to evaluate the effect of increasing APAP dose
LC-MRM chromatograms for α-TMCA, β-TMCA, and taurocholic acid (TCA) in rat plasma show good resolution obtained and highlight the usefulness of this method to monitor these isomers
Summary
Bile acids play many roles crucial for metabolism and liver health. They are formed from cholesterol through a series of enzymatic reactions and they represent the primary pathway for cholesterol catabolism [1]. Bile acids emulsify fat from our diet and help absorb lipids and cholesterol [2]. Primary bile acids, such as cholic acid (CA) and chenodeoxycholic acid (CDCA) in humans and α-muricholic acid (α-MCA) and β-muricholic acid (β-MCA) in rodents, are synthesized in the liver. Most bile acids are reabsorbed in the liver, conjugated again, and excreted in the bile to complete the enterohepatic circulation [2,3]
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