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Pyrrole‐protein adducts, a mechanism‐based biomarker of pyrrolizidine alkaloid induced hepatotoxicity

Pyrrolizidine alkaloids (PAs) are among the most hepatotoxic phytotoxins present in about 3% of the flowering plants. Ingestion of PAs causes hepatic sinusoidal obstruction syndrome (HSOS), characterized by primary sinusoidal endothelial cell damage. The hepatic cytochrome P450‐mediated metabolic activation of PAs leading to the formation of pyrrole‐protein adducts has been considered the major pathway in initiating PA‐induced liver injury (PA‐ILI). Our previous studies provided evidence to support that pyrrole‐protein adducts can potentially serve as a biomarker of PA exposure and PA‐ILI. The present study aimed to 1) investigate the correlation between the level of pyrrole‐protein adducts formed from the metabolism of different PAs and their hepatotoxic potency; and 2) characterize the binding specificity, dose‐response, and elimination kinetics of blood pyrrole‐protein adducts in rats. Two PA‐containing herbs Crotalaria sessiliflora (containing senecionine and seneciphylline) and Gynura segetum (containing monocrotaline), and a representative toxic PA (monocrotaline) were used for the study. We observed that there was a good correlation between the level of dose‐dependent hepatotoxicity (determined by the elevation of serum ALT) and the formation of pyrrole‐protein adducts in the liver of rats treated with different PAs. There was also a good correlation between the hepatic and the blood on the level of pyrrole‐protein adduct formation. The results indicated that pyrrole‐protein adducts were formed dose‐dependently in all the monocrotaline‐treated rat blood protein fractions, including hemoglobin (Hb), plasma, albumin, and residual protein fractions, with the highest level of pyrrole‐protein adducts in Hb fraction. The elimination half‐lives of pyrrole‐protein adducts in rat Hb, plasma proteins, albumin, and residual proteins were determined to be 12.08 ± 1.06, 2.81 ± 0.08, 2.54 ± 0.11, and 2.93 ± 0.04 days, respectively. These findings suggest that pyrrole‐Hb adduct is a potential minimal invasive biomarker of PA exposure and PA‐ILI.