138
ple, trypsin cleaves peptides on the C-terminal side of arginine or lysine residues.
Peptidases also function as amidases since they cleave the amide linkage between
adjacent amino acids.
Epoxide Hydrolase The trans addition of water to alkene epoxides and arene oxides
(oxiranes) is catalysed by epoxide hydrolase. Epoxide hydrolase is present in almost
all tissues, including the liver, lung, kidney, skin, intestine, colon, testis, ovary,
spleen, thymus, brain and heart. The five distinct forms of epoxide hydrolase present in mammals include microsomal epoxide hydrolase (mEH), soluble epoxide
hydrolase (sEH), cholesterol epoxide hydrolase, LTA4 hydrolase and hepoxilin
hydrolase. As their names imply, cholesterol epoxide hydrolase, LTA4 hydrolase,
and hepoxilin hydrolase exclusively hydrolyze endogenous epoxides, but have no
particular role in the detoxification of xenobiotic oxides. LTA4 hydrolase is distinct
from the other epoxide hydrolases in that it is a bifunctional zinc metalloenzyme
that has both epoxide hydrolase and peptidase activities as well as because of the
two hydroxyl groups introduced during the conversion of LTA4 to LTB4. Many
epoxides and oxides are intermediates formed during the cytochrome P450dependent oxidation of aromatic and unsaturated aliphatic xenobiotics. These
metabolites which may otherwise bind to proteins and nucleic acids and cause cellular toxicity and genetic mutations are removed by epoxide hydrolases, particularly
mEH and sEH. They rapidly convert the potentially toxic metabolites to the corresponding dihydrodiols, which are less reactive and easier to excrete. Because of
these activities epoxide hydrolases are widely considered as a group of detoxification enzymes (Parkinson et al. 2013).
5.2.3 Reductive Reactions
Certain metals (e.g. pentavalent arsenic) and xenobiotics with an aldehyde, ketone,
disulfide, sulfoxide, quinone, N-oxide, alkene, azo or nitro group often undergo
reduction reaction, although it is sometimes difficult to ascertain whether the reaction proceeds enzymatically or non-enzymatically by interaction with reducing
agents (such as the reduced forms of glutathione, FAD, FMN and NAD(P))
(Parkinson et al. 2013).
Azo- and Nitro-Reductions During azo-reduction, the nitrogen–nitrogen double
bond is sequentially reduced and cleaved to produce two primary amines, using four
reducing equivalents. Nitro-reduction requires six reducing equivalents, which are
consumed in three sequential reactions, for the transformation of nitrobenzene to
aniline. Azo- and nitro-reductions can be catalysed by enzymes of intestinal flora
(Fig. 5.3), two liver enzymes cytochrome P450 (has the capacity to reduce xenobiotics under low oxygen or anaerobic conditions) and NAD(P)H-quinone oxidoreductase (a cytosolic flavoprotein, also known as DT-diaphorase), and interactions
with reducing agents (reduced forms of glutathione, NADP, etc.). Under certain
circumstances, a third liver enzyme, aldehyde oxidase, may also catalyse azo- and
nitro-reduction reactions (Parkinson et al. 2013).
S. Sudhakaran et al.
ple, trypsin cleaves peptides on the C-terminal side of arginine or lysine residues.
Peptidases also function as amidases since they cleave the amide linkage between
adjacent amino acids.
Epoxide Hydrolase The trans addition of water to alkene epoxides and arene oxides
(oxiranes) is catalysed by epoxide hydrolase. Epoxide hydrolase is present in almost
all tissues, including the liver, lung, kidney, skin, intestine, colon, testis, ovary,
spleen, thymus, brain and heart. The five distinct forms of epoxide hydrolase present in mammals include microsomal epoxide hydrolase (mEH), soluble epoxide
hydrolase (sEH), cholesterol epoxide hydrolase, LTA4 hydrolase and hepoxilin
hydrolase. As their names imply, cholesterol epoxide hydrolase, LTA4 hydrolase,
and hepoxilin hydrolase exclusively hydrolyze endogenous epoxides, but have no
particular role in the detoxification of xenobiotic oxides. LTA4 hydrolase is distinct
from the other epoxide hydrolases in that it is a bifunctional zinc metalloenzyme
that has both epoxide hydrolase and peptidase activities as well as because of the
two hydroxyl groups introduced during the conversion of LTA4 to LTB4. Many
epoxides and oxides are intermediates formed during the cytochrome P450dependent oxidation of aromatic and unsaturated aliphatic xenobiotics. These
metabolites which may otherwise bind to proteins and nucleic acids and cause cellular toxicity and genetic mutations are removed by epoxide hydrolases, particularly
mEH and sEH. They rapidly convert the potentially toxic metabolites to the corresponding dihydrodiols, which are less reactive and easier to excrete. Because of
these activities epoxide hydrolases are widely considered as a group of detoxification enzymes (Parkinson et al. 2013).
5.2.3 Reductive Reactions
Certain metals (e.g. pentavalent arsenic) and xenobiotics with an aldehyde, ketone,
disulfide, sulfoxide, quinone, N-oxide, alkene, azo or nitro group often undergo
reduction reaction, although it is sometimes difficult to ascertain whether the reaction proceeds enzymatically or non-enzymatically by interaction with reducing
agents (such as the reduced forms of glutathione, FAD, FMN and NAD(P))
(Parkinson et al. 2013).
Azo- and Nitro-Reductions During azo-reduction, the nitrogen–nitrogen double
bond is sequentially reduced and cleaved to produce two primary amines, using four
reducing equivalents. Nitro-reduction requires six reducing equivalents, which are
consumed in three sequential reactions, for the transformation of nitrobenzene to
aniline. Azo- and nitro-reductions can be catalysed by enzymes of intestinal flora
(Fig. 5.3), two liver enzymes cytochrome P450 (has the capacity to reduce xenobiotics under low oxygen or anaerobic conditions) and NAD(P)H-quinone oxidoreductase (a cytosolic flavoprotein, also known as DT-diaphorase), and interactions
with reducing agents (reduced forms of glutathione, NADP, etc.). Under certain
circumstances, a third liver enzyme, aldehyde oxidase, may also catalyse azo- and
nitro-reduction reactions (Parkinson et al. 2013).
S. Sudhakaran et al.