1.

Direct-acting Compound
-do not require chemical
transformation for carcinogenecity
2. Indirect-acting Compound or
Procarcinogenesis
- require metabolic conversion in
vivo to produce ultimate carcinogens
capable of transforming cells
Most direct-acting compounds and
ultimate carcinogens are highly
reactive electrophiles that can react
with nucleophilic site the cell
The electrophilic reactions may attack
several electron-rich sites in the target
cells including DNA, RNA, and proteins,
thus sometimes producing lethal
damage
Metabolic Activation of
Carcinogens
 dependent mono-oxygenase
- metabolize most of the known
carcinogens
- the genes that encode these enzymes are
polymorphic
- essential for the activation of
procarcinogens, thus the susceptibility to
carcinogenesis is regulated in part by
polymorphism in the genes that encode
these enzymes
CYP1A1 the product of P-450
- metabolizes polycyclic aromatic
hydrocarbons

Approximately 10% of the white population has a

highly inducible form of this enzyme that is
associated with an increased risk of lung
cancer in smokers
 - polymorphic and involved in the
detoxification of polycyclic aromatic
hydrocarbons

50% of white incur a higher risk of lung

and bladder cancer but if only
exposed to tabacco smokes
The DNA is the primary target of
chemical carcinogens

The interaction of each chemical

carcinogen with DNA is not completely
random and each class of carcinogens
tend to produce a limited pattern of
DNA damage
Carcinogen-induced changes in DNA
do not necessarily lead to initiation
because most types of DNA damage
can be repaired by cellular enzymes
Environmentally induced insults to DNA
are common than the occurrence of
cancer as long as repair mechanism are
intact
Ex. Xeroderma pigmentosa
- rare hereditary disorders
- associated with a defect in DNA repair and a greatly
increased vulnerability to skin cancer caused by
ultraviolet lights and some chemicals
Unrepaired alterations in the DNA are
essential first steps in the process of
initiation
For initiation to occur, carcinogen-altered
cells must undergo at least one cycle of
proliferation so that the change in DNA
becomes fixed or permanent
The carcinogenecity of some chemicals
is augmented by subsequent
administration of promoters (phorbol
esters, hormones, phenols, and
drugs) that by themselves are
nontumorigenic
Application of promoters leads to
proliferation and clonal expansion of
initiated cells that respond differently to
promoters
Forced to proliferate, the initiated clone
cells suffer additional mutations,
developing eventually to malignant tumor