-Biotransformation is one of the processes which influence the bioaccumulation of chemicals. The enzymatic action of metabolism involves two processes, i.e. the binding of the substrate to the enzyme followed by a catalytic reaction, which are described by the Michaelis-Menten constant (K m) and the maximum rate (V max). Here, we developed Quantitative Structure-Activity Relationships (QSARs) for Log(1/K m) and LogV max for substrates of four enzyme classes. We focused on oxidations catalysed by alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), flavin-containing monooxygenase (FMO) and cytochrome P450 (CYP) in mammals. The chemicals investigated were xenobiotics, including alcohols, aldehydes, pesticides and drugs. We applied general linear models for this purpose, employing descriptors related to partitioning, geometric characteristics, and electronic properties of the substrates, which can be interpreted mechanistically. The explained variance of the QSARs varied between 20% and 70%, and it was larger for Log(1/K m) than for LogV max. The increase of 1/K m with compound logP and size suggests that weak interactions are important, e.g. by substrate binding via desolvation processes. The importance of electronic factors for 1/K m was described in relation to the catalytic mechanism of the enzymes. V max was particularly influenced by electronic properties, such as dipole moment and energy of the lowest unoccupied molecular orbital. This can be explained by the nature of the catalysis, characterised by the cleavage and formation of covalent or ionic bonds (strong interactions). The present study may be helpful to understand the underlying principles of the chemical specific activity of four important oxidising enzymes.

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In bioaccumulation models, biotransformation is one of the processes decreasing the concentration of chemicals in an organism. In order to be metabolized, a compound needs to bind to an enzyme. In this study, we derived relationships between binding affinity and lipophilicity, expressed as Log (1/K(m)) and Log K(ow), respectively. We focused on oxidations in mammals catalyzed by alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), flavin-containing monooxygenase (FMO), and cytochrome P450 (CYP) enzymes. For all regressions, 1/K(m) increased with compound K(ow), which can be understood from the tendency to biotransform lipophilic compounds into more polar, thus more easily excretable metabolites. Lipophilicity was relevant to the binding of most of the substrate classes of ADH, ALDH, and CYP. The resulting slopes had 95% Confidence Intervals covering the value of 0.63, typically noted in protein-water distribution (Log K(pw)) and Log K(ow) regressions. A reduced slope (0.2-0.3) was found for FMO: this may be due to a different reaction mechanism involving a nucleophilic attack. The general patterns of metabolism were mechanistically interpreted in terms of partitioning theory. Information on the overall principles determining biotransformation may be helpful in predicting metabolic rates.

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