Læknablaðið - 15.10.1983, Qupperneq 28

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LÆKNABLAÐID
late metabolism. Briefly, there are three ge-
neral mechanisms accounting for the modula-
tion of metabolism by inhibitors or inducers
(73):
a. Stimulation of cellular metabolism which
results in increased detoxification and/or acti-
vation. Modulation of this type may occur in
at least two ways: (1) The modulator increases
monooxygenase activity. For example, a wide
range of compounds including polycyclic aro-
matic hydrocarbons, phenobarbital, flavones,
hydrogenated hydrocarbons and indoles can
induce increases in monooxygenase activities.
The overall effect is a change in the relative
proportion of detoxification versus metabolic
activation and therefore the overall tumor
incidence may be modulated (32). (2) The
modulator enhances the activities of enzymes
other than the cytochrome P-450 microsomal
monooxygenases, that catalyze the trapping
of reactive metabolites by conjugation with
exogenous substrates (e.g. glutathione, glucu-
ronic acid, etc.).
b. Direct blocking of enzymatic activation
of the chemical carcinogen to form the
ultimate carcinogenic metabolite(s). For
example, disulfiram inhibits dimethylhydra-
zine-induced neoplasia of the large bowel (73)
by reducing the rate of conversion of dime-
thylhydrazine to a reactive metabolite.
c. Direct scavenging of the reactive meta-
bolites by inhibitors, such as glutathione.
The use of various chemical modulators has
contributed significantly to our understanding
of the metabolism and disposition of chemical
carcinogens. Additionally, with extended re-
search into the mechanism of action of these
agents, the use of such modulators may, in the
future, aid in the prevention of some chemical-
ly induced tumors. However, at present, it
would be premature to state that modulators
will be generally effective in preventing can-
cer induction by even some chemicals.
3. Organ and Species Differences. Levels
and substrate specificities of the phase 1 and
phase 2 metabolizing enzymes vary among
strains and species and between tissues (38).
Thus, the metabolic profiles resulting in both
activation and detoxification could conceiv-
ably have marked species-, strain-, or tissue-
specific differences. For example, there are
multiple forms (isoenzymes) of cytochrome P-
450 dependent monooxygenases each of
which exhibits its own regiospecificity and
stereospecificity toward a particular substrate
(32). These isoenzymes vary among different
tissues, strains and species. Glutathione S-
transferases and UDP-glucuronyltransferases
also occur in multiple forms in different
tissues, strains, or species (38). Additionally,
the activity of each metabolizing enzyme in a
specified tissue of the same strain could vary
widely depending on the age, sex, nutritional
factors, hormonal status, or other factors (38).
For these reasons, without knowing the en-
zyme profile, it is impossible to quantitativeiy
extrapolate the metabolic activation of chemi-
cal carcinogens from in vitro to in vivo, or
from.laboratory animals to humans. However,
such metabolic comparisons between animal
species and man are very useful for qualitative
assessments of the relevance of a specific
animal model to the study of human risk from
these compounds.
B. Interactions with Macromolecules
1. DNA Alterations and Repair. It is generally
believed that the initial event in the onset of
chemically-induced tumorigenesis is the cova-
lent interaction of electrophilic species with
nucleophilic centers within the cell (43). Alt-
hough macromolecules, such as RNA, protein,
and lipid containing membranes are targets
for activated carcinogens, the current consen-
sus is that the critical site for carcinogen
binding is DNA. Several observations support
this hypothesis: a) most carcinogens are muta-
gens and mutations are detectable alterations
in DNA (43); b) certain genetic diseases that
are characterized by defective DNA repair,
such as xeroderma pigmentosum, predispose
affected individuals to cancer and increase
their sensitivity to mutagens (2); and c) DNA
damage that leads to mutations in human cells
has been implicated in the transformation of
these cells to a tumorigenic phenotype (41).
The interaction of chemical carcinogens
with DNA has been postulated to induce a
tumorigenic phenotype through either of two
mechanisms: a) by directly altering the genetic
information through a somatic mutation; or b)
by altering the expression of genes through an
epigenetic mechanism (39). It should be emp-
hasized that both of these mechanisms are
also compatible with DNA damage caused by
UV and ionizing radiation, thus providing a
common framework between chemical- and
radiation-induced cancers. Tumorigenesis by