US EPA

3481440 

Journal Article 

Theoretical insights into the reductive metabolism of CCl4 by cytochrome P450 enzymes and the CCl4-dependent suicidal inactivation of P450 

Li, XX; Zheng, QC; Wang, Y; Zhang, HX 

2014 

Yes 

Dalton Transactions (Online)
ISSN: 1477-9234 

43 

39 

14833-14840 

English 

25164482 

10.1039/c4dt02065k 

The anaerobic metabolism of CCl4 by P450 enzymes was investigated using quantum chemical calculations. It was found that under anaerobic conditions, the substrate CCl4 might undergo one or two subsequent one-electron reductions to generate different reactive metabolites, trichloromethyl radical (˙CCl3) and dichlorocarbene (:CCl2) respectively. Meanwhile, it was the reduced ferrous haem complex rather than the unreduced ferric haem complex that could directly achieve such reductions. Based on the formation of the former reactive metabolite, a further one-electron reduction could take place with the assistance of a proton to yield the latter reactive species, i.e., a further reductive dechloridation of ˙CCl3 could take place via a novel SE3 mechanism. In addition, the ˙CCl3 species was capable of binding covalently to the meso-carbon atom of the prosthetic group, leading to the suicidal destruction of P450 enzymes. Whereas the :CCl2 species was involved in the CCl4-dependent reversible P450 inhibition as its hydrolysis product, CO, but was not significantly involved in the CCl4-dependent irreversible P450 destruction. It is obvious that the reductive metabolism of CCl4 to reactive intermediates by P450 enzymes is an essential prerequisite for its toxicity.