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5.2
Biotransforming Enzymes in Humans
In the case of humans, all those molecules which the body does not recognize as its
own are considered as ‘foreign’ or xenobiotics. This section explains the biotransformation of xenobiotics by respective enzymes, thus lessening their toxic effects
and easily removing them from the body.
Today all living beings of the earth are constantly and unavoidably exposed to
xenobiotics, which include both manufactured and naturally occurring chemicals
such as industrial chemicals, pesticides, drugs, pollutants, alkaloids, secondary
plant metabolites, and toxic substances. Xenobiotics are readily absorbed by the
human body because of their lipophilic property. It is due to this physical property
that the homeostasis becomes altered. Consequently, there comes the role of biotransformation enzymes, which aid in the elimination of xenobiotics by converting
them to hydrophilic compounds. The process of biotransformation ends up with the
change in properties of foreign molecules, i.e. from those preferring absorption
(lipophilicity) to those which are easily eliminated either through urine or faeces
(hydrophilicity).
Having a broad substrate specificity, the biotransforming enzymes metabolize a
wide range of endogenous compounds such as acetone, ethanol, steroid hormones,
bilirubin, bile acids, fatty acids, eicosanoids, vitamins A and D, etc. Some of these
enzymes are either expressed constitutively or are induced by the xenobiotic itself.
The rates of xenobiotic biotransformation among individuals may vary depending
upon the amino acid sequence, i.e. the structure of a given biotransforming enzyme.
In general, a variant form of a xenobiotic biotransforming enzyme (allelic variant
or an allelozyme) has diminished enzymatic activity compared with that of the wildtype enzyme, although this is not always the case. However, the impact of amino
acid substitution on the catalytic activity of a xenobiotic biotransforming enzyme is
usually substrate-dependent (Parkinson et al. 2013). The reactions catalysed by
xenobiotic biotransforming enzymes are generally divided into two groups: Phase I
and Phase II (Table 5.1).
5.2.1 Phase I Reactions
Phase I reactions mainly involve three reactions – oxidation, reduction and hydrolysis. These reactions introduce a functional group (−OH, −SH, −NH 2 or –COOH),
and usually end up in the formation of slightly hydrophilic compounds. The functional groups added during phase I biotransformation form the site for phase II
biotransformation.
Oxidative Reactions Oxidation is the most prevalent and an important way of
metabolizing xenobiotics. It includes withdrawal of an electron, followed by addition of oxygen into the molecule. Molecular oxygen most often forms the source
and in some cases the oxygen is obtained from water. Most organic compounds
undergo single-electron or double-electron redox reactions. Some undergo a 4e5 Biotransformation Enzymes
5.2
Biotransforming Enzymes in Humans
In the case of humans, all those molecules which the body does not recognize as its
own are considered as ‘foreign’ or xenobiotics. This section explains the biotransformation of xenobiotics by respective enzymes, thus lessening their toxic effects
and easily removing them from the body.
Today all living beings of the earth are constantly and unavoidably exposed to
xenobiotics, which include both manufactured and naturally occurring chemicals
such as industrial chemicals, pesticides, drugs, pollutants, alkaloids, secondary
plant metabolites, and toxic substances. Xenobiotics are readily absorbed by the
human body because of their lipophilic property. It is due to this physical property
that the homeostasis becomes altered. Consequently, there comes the role of biotransformation enzymes, which aid in the elimination of xenobiotics by converting
them to hydrophilic compounds. The process of biotransformation ends up with the
change in properties of foreign molecules, i.e. from those preferring absorption
(lipophilicity) to those which are easily eliminated either through urine or faeces
(hydrophilicity).
Having a broad substrate specificity, the biotransforming enzymes metabolize a
wide range of endogenous compounds such as acetone, ethanol, steroid hormones,
bilirubin, bile acids, fatty acids, eicosanoids, vitamins A and D, etc. Some of these
enzymes are either expressed constitutively or are induced by the xenobiotic itself.
The rates of xenobiotic biotransformation among individuals may vary depending
upon the amino acid sequence, i.e. the structure of a given biotransforming enzyme.
In general, a variant form of a xenobiotic biotransforming enzyme (allelic variant
or an allelozyme) has diminished enzymatic activity compared with that of the wildtype enzyme, although this is not always the case. However, the impact of amino
acid substitution on the catalytic activity of a xenobiotic biotransforming enzyme is
usually substrate-dependent (Parkinson et al. 2013). The reactions catalysed by
xenobiotic biotransforming enzymes are generally divided into two groups: Phase I
and Phase II (Table 5.1).
5.2.1 Phase I Reactions
Phase I reactions mainly involve three reactions – oxidation, reduction and hydrolysis. These reactions introduce a functional group (−OH, −SH, −NH 2 or –COOH),
and usually end up in the formation of slightly hydrophilic compounds. The functional groups added during phase I biotransformation form the site for phase II
biotransformation.
Oxidative Reactions Oxidation is the most prevalent and an important way of
metabolizing xenobiotics. It includes withdrawal of an electron, followed by addition of oxygen into the molecule. Molecular oxygen most often forms the source
and in some cases the oxygen is obtained from water. Most organic compounds
undergo single-electron or double-electron redox reactions. Some undergo a 4e5 Biotransformation Enzymes