Conformational aspects of glutathione conjugates of chlorinated alkenes: a computational study.
The nephrotoxicity of halogenated alkenes is due to the beta-lyase mediated bioactivation of the hepatic glutathione (GS) conjugate to mutagenic or cytotoxic reactive species in kidney. Experimental evidence obtained for regioisomers and geometric isomers of haloalkene GS conjugates indicates that different isomers may be metabolized and excreted at different rates, follow different metabolic pathways, and exhibit different toxicities. Computational methods were applied in the present work to a conformational study of GS-haloalkene conjugates to determine the relative stabilities of possible regioisomers and geometric isomers of the conjugates. The halogenated alkenes studied were 1,1,2-trichloroethylene (TCE), hexachloro-1,3-butadiene (HCBD), and 1,1,2-trichloro-3,3,3-trifluoro-1-propene (TCTFP). Calculated energies of GS conjugate products were used to approximately infer relative product abundance under synthetic and in vivo conditions. This approach neglects differential solvent effects and enzyme selectivity and assumes a late transition state for GS conjugation and/or some thermodynamic control of the conjugation process. Relative population predictions of GS conjugate isomers, based on computed energies, were in agreement with experimental synthetic and in vivo isomer determinations in the case of TCE, where careful analytical characterization of the isomers was definitive. In the case of HCBD, where analytical determinations were not performed and isomer assignments were based on general reactivity concepts, calculations from the present study supported one GS conjugate isomer assignment and disagreed with the other. Finally, in the case of TCTFP, the calculations predicted that three isomers would have similar populations, whereas only two were detected in the experimental study.
Shim
J Y
JY
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Richard
A M
AM
D000475:Alkenes / Q000737:chemistry*; D002070:Butadienes / Q000737:chemistry; D017402:Chlorofluorocarbons / Q000737:chemistry; D018360:Crystallography, X-Ray; D005978:Glutathione / Q000737:chemistry*; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D014241:Trichloroethylene / Q000737:chemistry
D000475:Alkenes; D002070:Butadienes; D017402:Chlorofluorocarbons; D006843:Hydrocarbons, Chlorinated; D012997:Solvents; D014241:Trichloroethylene; C060270:1,1,2-trichloro-3,3,3-trifluoro-1-propene; C001335:hexachlorobutadiene; D005978:Glutathione