AbstractThe polysubstrate monooxygenase (PSMO) system response to hydrophobic xenobiotics is both intensive in oxidizing power and extensive in enzyme quantity. Under in vitro pseudo‐first‐order rate conditions the extensive properties become irrelevant, and the intensive rate‐determining step depends on chemical structure. Xenobiotics react with PSMO either as inducers (adaptation domain) or as substrates (reaction domain) to produce “intended” hydroxylation, but “accidental” oxidations may also occur. Both the induction of intensive oxidizing power in the adaptation domain and the efficiency of reaction in the reaction domain depend on the strength of the weakest CH bond in the xenobiotic, consistent with either a free radical or an ionic SE2 reaction process. Only the ionic SE2 mechanism is sensitive to the electrical charge on the carbon atom of the weakest CH bond. In this study systematic “treatment” of simple hydrocarbon structures by adjacent polarizing heteroatoms N, Cl, and O inhibited substrate metabolism in direct proportion to their polarizing power. With this evidence of preferential SE2 behaviour, a QSAR is proposed that allows prediction of four types of disease end points. These arise as combination of conditions of intended or accidental oxidations combined with release of metabolites into cyt