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 (Km) and the maximum rate (Vmax). Here, we developed Quantitative Structure-Activity Relationships (QSARs) for Log(1/Km) and LogVmax 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/Km) than for LogVmax. The increase of 1/Km 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/Km was described in relation to the catalytic mechanism of the enzymes. Vmax 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.