members with some minor contributions from CYP1A1, CYP2B6, and CYP2C8. At
a quantitative level, the affinity towards the substrate, and hence the rate of the
reaction, is positively correlated with its lipophilicity. In other words, very polar
drugs (logP <0) are rarely recognized by CYPs and therefore frequently escape
oxidative metabolism in the human body. Of the aforementioned isoforms, CYP3A4
is the most promiscuous one exhibiting broad substrate selectivity. Despite some
overlap in the selectivity between the isoforms, structural features of the substrate,
such as size, planarity, and presence of charge center, result in preference for a
specific enzyme [6].
As far as type of CYP-mediated reactions are concerned, the most prominent
transformations include hydroxylation of aliphatic and aromatic carbon atoms, e.g.,
hydroxylation of in the isobutyl group of ibuprofen (IBU) (yielding a mixture of
primary, secondary, and tertiary alcohols) or the hydroxylation of the dichlorophenyl
ring in diclofenac (DCF) (Fig. 1). A subtype of the former reaction is the carbon
hydroxylation at the benzylic position being favored due to stabilization of an
intermediate in the catalytic cycle. When the oxygenation of the carbon atom occurs
on the α-carbon of the alkyl group attached to a heteroatom, the chemically unstable
intermediate (a hemiacetal in case of O-alkyl; a hemiaminal in case of N-alkyl)
decomposes to yield the dealkylated metabolite (metoprolol in Fig. 1). In the former
case, this unmasks an alcohol resulting a considerably more polar compound. A
further CYP-mediated reaction at a carbon center is the epoxidation of double bonds.
Although in most instances the epoxides are chemically reactive and undergo
subsequent reactions, the formation of the symmetrical epoxide of carbamazepine
(CBZ) is an example of a metabolite being sufficiently stable to be excreted into
human urine (Fig. 1).
Apart from oxidizing carbon in various structural environments, CYPs are also
capable of oxygenating heteroatoms such as nitrogen and sulfur. As such, aromatic
Fig. 1 CYP-mediated carbon oxidations: aliphatic hydroxylation of ibuprofen, aromatic hydroxylation of diclofenac, heteroatom dealkylations of metoprolol, and epoxidation of carbamazepine
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A. Sauvêtre et al.
a quantitative level, the affinity towards the substrate, and hence the rate of the
reaction, is positively correlated with its lipophilicity. In other words, very polar
drugs (logP <0) are rarely recognized by CYPs and therefore frequently escape
oxidative metabolism in the human body. Of the aforementioned isoforms, CYP3A4
is the most promiscuous one exhibiting broad substrate selectivity. Despite some
overlap in the selectivity between the isoforms, structural features of the substrate,
such as size, planarity, and presence of charge center, result in preference for a
specific enzyme [6].
As far as type of CYP-mediated reactions are concerned, the most prominent
transformations include hydroxylation of aliphatic and aromatic carbon atoms, e.g.,
hydroxylation of in the isobutyl group of ibuprofen (IBU) (yielding a mixture of
primary, secondary, and tertiary alcohols) or the hydroxylation of the dichlorophenyl
ring in diclofenac (DCF) (Fig. 1). A subtype of the former reaction is the carbon
hydroxylation at the benzylic position being favored due to stabilization of an
intermediate in the catalytic cycle. When the oxygenation of the carbon atom occurs
on the α-carbon of the alkyl group attached to a heteroatom, the chemically unstable
intermediate (a hemiacetal in case of O-alkyl; a hemiaminal in case of N-alkyl)
decomposes to yield the dealkylated metabolite (metoprolol in Fig. 1). In the former
case, this unmasks an alcohol resulting a considerably more polar compound. A
further CYP-mediated reaction at a carbon center is the epoxidation of double bonds.
Although in most instances the epoxides are chemically reactive and undergo
subsequent reactions, the formation of the symmetrical epoxide of carbamazepine
(CBZ) is an example of a metabolite being sufficiently stable to be excreted into
human urine (Fig. 1).
Apart from oxidizing carbon in various structural environments, CYPs are also
capable of oxygenating heteroatoms such as nitrogen and sulfur. As such, aromatic
Fig. 1 CYP-mediated carbon oxidations: aliphatic hydroxylation of ibuprofen, aromatic hydroxylation of diclofenac, heteroatom dealkylations of metoprolol, and epoxidation of carbamazepine
226
A. Sauvêtre et al.