Læknablaðið - 15.10.1983, Page 26

250
LÆK.NABLADID
carcinogens include a wide variety of agents
(Figure 1). These include polycyclic aromatic
hydrocarbons and their derivatives, aromatic
amines, azo dyes, nitrosamines, organic sol-
vents such as carbon tetrachloride, arrd some
metals. These agents may occur naturally or
may result from industrial processes, social
activities, or may be ingested as drugs or food
additives. Most organic chemical carcinogens,
and possibly some inorganic metal complexes,
require metabolic activation in order to exert
their tumor-induction properties. Miller and
Miller (44) proposed that the ultimate carcino-
genic forms of the organic chemical carcino-
gens are electrophilic (electron seeking) reac-
tants which bind covalently with the target
cellular macromolecules such as DNA and
proteins.
In general, the enzymes involved in metabo-
lizing chemical carcinogens are part of the
same system responsible for detoxification of
drugs and foreign compounds. These enzymes
can be divided into two groups which convert
the chemicals into either phase 1 or phase 2
metabolites. Phase 1 metabolites are the
primary oxidation product which are some-
what more water solubie than the substrate
and thus more easily transported through
cells. These metabolites are then conjugated
with various soluble cellular constituents to be-
come more available for excretion from the
body. This process is considered phase 2
metabolism (66, 77).
The reactions which occur in either phase 1
or phase 2 require specific enzymes (Table 1).
When a chemical carcinogen interacts with
OR’ CHz-O-CO-R 00
co
Pyrrolizidine alkaloids Aflatoxin B|
(senecio, crotolaria and (aspergillus flavus
heliotropium genera) strain)
P-glucosyl-0-CH2-N = N-CH3 °-\ &
0 ch2-ch=ch2
Cycasin Safrole
(cycad nuts) (oil of sassafras)
Figure 1. Examples of chemical carcinogens.
Table 1
Phase 1
I. Cytochrome P-450 containing enzymes, and
flavoprotein NADPH-cytochrome P-450 reduc-
tase catalyze epoxidation of aromatic rings or
olefinic double bonds, produce hydroxylation of
aromatic rings or alkyl chains, perform oxidati-
ve dealkylation, and N-oxidation (38). This
system occurs mainly in the endoplasmic reticu-
lum of liver, kidney, lung, intestine, and is also
present in many other tissues. These enzymes
are in multiple forms which exhibit different or
overlapping substrate-specificity (38).
II. Epoxide hydrolase catalyzes the hydrolysis of
arene oxide into the írans-dihydrodiol metaboli-
te.
III. Dehydrogenase, microsomal flavoprotein mix-
ed-function oxidase and xanthine oxidase cata-
lyze the reduction of nitrosaromatics to nitroso-
arenes, N-hydroxy amines, and arylamines, and
reduction of azo compounds to amines.
Phase2
I. Glutathione S-transferases catalyze the conju-
gation reaction between glutathione and a
variety of electrophilic compounds such as
arene oxide. These enzymes exist in multiple
forms (38).
II. UDP-Glucuronyltransferases catalyze the con-
jugation reaction between glucuronic acid with
substrates such as phenol and bilirubin. These
enzymes are also found in multiple forms (38).
III. Sulfotransferase catalyzes sulfate ester forma-
tion.
IV. N-Acyltransferases catalyze N-acetylation and
N.O-acyltransfer of aromatic amines and aryl
hydroxamic acids.