Xenobiotic Geometry and Media pH Determine Cytotoxicity through Solubility

Le résumé fourni par la source

Polychlorinated biphenyls (PCBs), a class of 209 individual congeners, have become persistent and ubiquitous environmental contaminants. The health impacts of PCBs, such as cancer, cardiovascular disease, developmental toxicity, and neurotoxicity, have been widely reported, but for many of these, the mechanisms of toxicity are still poorly understood. Many mechanistic studies involve cultured cells where the biological activity is dependent upon the solubility of the xenobiotic. In the present study, we investigated the factors that determine solubility as measured by diffraction spectroscopy and have modeled, with semiempirical and ab initio molecular orbital methods, the dihedral angle and calculated the dipole moment of a series of monofluorinated analogues (F-PCBs 3) of 4-chlorobiphenyl (PCB 3) as model compounds in vacuum and in water. We found a strong positive correlation between the dihedral angle, the rotation energy, the cavitation energy, the solubility, and the cytotoxicity in three human cell lines. The dipole moment was of minor influence. We also determined the influence of pH changes in a medium containing 10% fetal bovine serum (FBS), changes that could be expected when cells in culture are removed from a CO 2 incubator even for a short time. We found that the solubility is strongly affected by the pH and that this effect is not reversed by subsequent pH readjustment. In a study examining cytotoxicity, we showed that the actual pH and the pH history of a medium containing FBS were of major influence. We suggest that pH-driven changes in the tertiary and quaternary structure of albumin are responsible. These observations have implications for studies of the biological activity of semisoluble compounds, like PCBs and related compounds.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.