A thermodynamic QSAR analysis of the polysubstrate monooxygenase responses to xenobiotic chemicals

Empirical quantitative structure activity relationships (QSAR) predict risk from exposure to xenobiotic chemicals as a dependence of inverse concentration on oil-water partition and electronic structural factors. This is equivalent, term by term to standard kinetic molecular transition state theory. When this transformed version is applied to the behaviour of the polysubstrate monooxygenase (PSMO) enzyme system, the rate of unintended behaviour depends directly on only two electronic factors. One is negative dependence on the strength of the weakest carbon-hydrogen (C-H) bond, a factor common to both ionic and free radical mechanisms. The second is a strong negative dependence on the polarization of this bond towards positive charge on the carbon, a factor relevant to ionic reactions. The risk of unintended oxidation reactions, in contrast, depends directly on these two factors because as the rate of intended hydroxylation is inhibited by strong or polar C-H bonds, alternative essentially 'accidental' oxidations occur. These are shown to lead to several different disease end points depending on the ratio of C-H bond strength to polarity.