Deuterium isotope effect in bioactivation and hepatotoxicity of chloroform

Cytochrome P-450 appears to catalyze the $\text{in}$$\text{vitro}$ formation of phosgene (COCl₂) from chloroform (CHCl₃) in rat liver microsomes, since this reaction is NADPH dependent and inhibited by carbon monoxide and SKF 525-A. Moreover, the cleavage of the C-H bond appears to be the rate-determining step in this process since deuterium labeled chloroform (CDCl₃) is biotransformed into COCl₂ slower than is CHCl₃. CDCl₃ was also less hepatotoxic than CHCl₃ suggesting that a similar pathway of metabolism is responsible for the hepatotoxic properties of chloroform.