A comprehensive characterization biotransformation of chlorinated paraffin by human and carp liver microsomes via liquid chromatography-high-resolution mass spectrometry and screening algorithm

Abstract

The chlorinated paraffin (CP) monomer 1,2,5,6,9,10-Hexachlorodecane (CP-4) was subjected to in vitro biotransformation using human and carp liver microsomes. Five types of CP-4 metabolites (OH–, keto-, enol-, aldehyde- and carboxy-CP-4) were identified in human liver microsomer while only mono-OH-CP-4 was found in the carp liver microsomes. Kinetic studies revealed that the formation of mono-, di-, tri-hydroxylated CP-4, keto-, enol-, and aldehyde-CP-4 in human liver microsomes was best described by substrate inhibition models, whereas the formation of carboxylated CP-4 metabolites best fit the Michaelis–Menten model. Notably, keto-CP-4, enol-CP-4 and aldehyde-CP-4 were the predominant metabolites. The estimated V_max values for these metabolites were significantly higher in the human liver microsomes than in the carp liver microsomes. The intrinsic hepatic clearance (CL_int) of CP-4 was higher in humans than in carp, indicating species-specific differences in its metabolism. This study also highlighted potential toxicity concerns, with computational predictions showing varying degrees of acute oral toxicity for CP-4 and its metabolites. These findings indicate significant species-specific differences in the biotransformation of CP-4, emphasizing the potential health and environmental risks associated with chlorinated paraffins and their metabolites, and underscore the need for further research to address these concerns.