Electron Acceptor Properties of DDT and Molecular Mechanism of Its Toxicity

This Chapter reports the empty-orbital electronic structure and experimental data of dissociative electron attachment (DEA) to the gas-phase molecules DDT (1,1'-(2,2,2-trichloroethane-1,1-diyl)bis(4-chlorobenzene)) and its principal metabolite DDE (1,1-bis-(4-chlorophenyl)-2,2-dichloroethene), which possesses good electron-withdrawing abilities. Electron transmission spectroscopy (ETS) is employed to study formation of temporary negative ions (TNIs) by electron addition to vacant molecular orbitals of neutral molecules. Fragments formed by dissociation of TNIs, in kinetic competition with extra electron detachment, were detected by means of DEA spectroscopy. The experimental findings are supported by density functional theory (DFT) calculations. According to ideas put forward by James Lovelock in the early sixties of the XX century, these findings play a vital role to describe toxic effects produced in vivo by free radical formation followed by deactivation of enzymes by chemicals with high electron affinity, as in the case of the model toxicant carbon tetrachloride (CCl4). The present DEA results indicate that, in close analogy with CCl4, a chlorine negative ion is effectively eliminated from DDT “activated” by capture of an extra electron. Provided that a similar process can take place in the cellular ambient under conditions of excess negative charge, this would gives rise to formation of DDE and the second most abundant metabolite DDD (1-chloro-4-[2,2-dichloro-1-(4-chlorophenyl) ethyl]benzene) through generation of intermediate dechlorinated radicals. Two possible mechanisms for attachment of an extra electron to DDT in cells are discussed. In the first one, where e– derives from the mitochondrial electron transport chain, DDD formation is associated with hydrogen atom abstraction from neighboring lipids by [DDT – Cl]• neutral radicals, eventually initiating chain reactions of peroxidation of biomembranes. In the second one, e– can originate from the catalytic cycle of cytochrome P450, where dechlorinated radicals can be tightly bound to an active center causing “suicide deactivation” of P450 enzymes.