Cytochrome P450 can also catalyze hydroxylation of a C-H bond a to the oxygen atom in both alcohols and ethers. However, in contrast to ethers, the primary oxidants of alcohols appear to be the dehydrogenase enzymes and not the cytochromes P450, as will be discussed later.

The O-dealkylation of ethers, while not encountered as frequently as N-dealkylation, is still a common metabolic pathway. Mechanistically, it is less controversial than N-dealkylation. It is generally believed to proceed by the HAT pathway (Figure 3). The product of the reaction is unstable, being a hemiacetal or hemiketal, which dissociates to generate an alcohol and an aldehyde or ketone.

Energetically, O-dealkylation is less favored than N-dealkylation.44 This is not surprising, as the greater electronegativity of oxygen relative to nitrogen would make abstraction of an a-hydrogen atom more difficult. Examples of drugs in which O-dealkylation plays a significant role are phenacetin (45),74 dextromethorphan (47),75 codeine (49),76 and metoprolol (51)77 (eqns [14]-[17]).

H3CH2CO-(\ /)-NHCOCH3 -HO-<\ />—nhcoch3 + ch3co

45 46

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