331
PAHs and Metabolic Pathways
PAH metabolic pathways and metabolic enzymes are very much complex and that
is why in vitro studies may not be appropriate to induce PAH metabolism and to
study the exact mechanism of PAH carcinogenesis in vivo [41–43]. Nevertheless,
the advantages of in vitro models cannot be ignored and are still used to determine
different/single metabolic pathway, interactions of signaling pathways, gene expression including cell biology, and promoter methylation in PAH carcinogenesis. Mice
models using knock-down genes have arisen as crucial tools to find out the action of
a specific gene in PAH activation [44–46].
PAH Activation by Cytochrome P450s
Everyday exposure of humans to various xenobiotics leads to activate CYPs, which
accounts for 75% of the total metabolic enzymes [47] and are also the main metabolic catalytic enzymes responsible to oxidize organic substances such as PAHs. All
the isoforms of CYP1 are monooxygenases, which donate an oxygen atom to produce oxidative epoxides [48]. CYP1A1, CYP1A2, and CYP1B1 belong to the family of CYP1 which has a crucial part in PAH activation [49, 50]. Many studies have
demonstrated that PAHs are catalyzed faster by CYP1A1 compared to other isoforms of CYP1 like CYP1A2, 2C9, 3A4, and 2C19. Remaining isoforms may not
have a role in PAH metabolism including CYP2A6, 2B6, 2C8, 2D6, 2E1, 3A5, 3A7,
and 4A11 [51, 52]. Instead of CYP1A2, endogenous CYP1A is found in lungs and
is extremely inducible by PAHs [53, 54]. The stimulation by PAHs may continue for
several days or even months, even though the exposure of PAHs has stopped long
before [43, 55, 56], which is considered an important phenomenon for cancer development [57].
Obesogenic EDCs
Fats are the major form of stored energy in the body preserved in adipocytes in the
adipose tissue, and the adipose tissue has been recognized to be controlled by the
endocrine system and may also work as an endocrine organ because of having the
ability to secrete hormones [58]. Interference in hormonal regulation of adipose tissue functions leads to an inappropriate deposits of fat which causes obesity
(Fig. 19.2). Reports are increasing which showed that some EDCs may also hamper
the control of metabolic processes and adipocyte function, resulting in an imbalance
in the body weight regulation, which can cause obesity [59–61]. Such chemical
which causes obesity has been named “obesogens” [62, 63]. 30 kg/m
2
body mass
index is considered obesity which has become a universal problem over recent
19 Role of Polycyclic Aromatic Hydrocarbons as EDCs in Metabolic Disorders
PAHs and Metabolic Pathways
PAH metabolic pathways and metabolic enzymes are very much complex and that
is why in vitro studies may not be appropriate to induce PAH metabolism and to
study the exact mechanism of PAH carcinogenesis in vivo [41–43]. Nevertheless,
the advantages of in vitro models cannot be ignored and are still used to determine
different/single metabolic pathway, interactions of signaling pathways, gene expression including cell biology, and promoter methylation in PAH carcinogenesis. Mice
models using knock-down genes have arisen as crucial tools to find out the action of
a specific gene in PAH activation [44–46].
PAH Activation by Cytochrome P450s
Everyday exposure of humans to various xenobiotics leads to activate CYPs, which
accounts for 75% of the total metabolic enzymes [47] and are also the main metabolic catalytic enzymes responsible to oxidize organic substances such as PAHs. All
the isoforms of CYP1 are monooxygenases, which donate an oxygen atom to produce oxidative epoxides [48]. CYP1A1, CYP1A2, and CYP1B1 belong to the family of CYP1 which has a crucial part in PAH activation [49, 50]. Many studies have
demonstrated that PAHs are catalyzed faster by CYP1A1 compared to other isoforms of CYP1 like CYP1A2, 2C9, 3A4, and 2C19. Remaining isoforms may not
have a role in PAH metabolism including CYP2A6, 2B6, 2C8, 2D6, 2E1, 3A5, 3A7,
and 4A11 [51, 52]. Instead of CYP1A2, endogenous CYP1A is found in lungs and
is extremely inducible by PAHs [53, 54]. The stimulation by PAHs may continue for
several days or even months, even though the exposure of PAHs has stopped long
before [43, 55, 56], which is considered an important phenomenon for cancer development [57].
Obesogenic EDCs
Fats are the major form of stored energy in the body preserved in adipocytes in the
adipose tissue, and the adipose tissue has been recognized to be controlled by the
endocrine system and may also work as an endocrine organ because of having the
ability to secrete hormones [58]. Interference in hormonal regulation of adipose tissue functions leads to an inappropriate deposits of fat which causes obesity
(Fig. 19.2). Reports are increasing which showed that some EDCs may also hamper
the control of metabolic processes and adipocyte function, resulting in an imbalance
in the body weight regulation, which can cause obesity [59–61]. Such chemical
which causes obesity has been named “obesogens” [62, 63]. 30 kg/m
2
body mass
index is considered obesity which has become a universal problem over recent
19 Role of Polycyclic Aromatic Hydrocarbons as EDCs in Metabolic Disorders