96
Environmental Toxicology
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Ref: 4365 MING-HO YU Chap-006 Page: 96 85-98
chemicals or certain drugs. For instance, CYP1A1 and CYP1A2 are induced in
smokers, while CYP2E1 is induced by ethanol and isoniazid, etc. Many studies
have shown increases in MFO enzymes from organisms following exposure to
xenobiotics. Such inducers of cytochrome P450 increase the rate of xenobiotic
biotransformation. As a consequence of this phenomenon, it would be
expected that there could be increases in the activation of procarcinogens to
DNA-reactive metabolites, leading to increased tumor formation. However, it
is not clear whether this is indeed the case in humans. In many instances, P450
induction does not necessarily enhance the biotransformation of the inducer.
6
Fish from waters that receive pulp-mill effluents have been shown to
respond to the effluents with increases in hepatic MFO activity, particularly
that of EROD.
11 In a recent study, a compound isolated from a bleached-kraft
mill effluent (tentatively identified as a chlorinated pterostilbene) was shown to
be capable of causing MFO induction in rainbow trout and in a hepatocyte cell
line.
12
6.7.2 GENETIC POLYMORPHISMS
Another characteristic feature of cytochrome P450s is the occurrence of genetic
polymorphism, resulting in enzyme levels and activities varying greatly between
different individuals. Genetic polymorphism includes defects in CYP2D6 and
variations in CYP1A2 activities. For example, three phenotypes are found in
CYP1A2: slow, medium, and rapid metabolizers. Research shows that this
phenomenon is related to susceptibility of individuals to certain types of cancer
– for example, increased bladder and colorectal cancer susceptibility for rapid
1A2 populations. Similarly, marked ethnic differences exist with CYP2D6, and
usually 1 to 10% of the population are poor metabolizers who may develop
less-aggressive forms of bladder cancer. Conversely, a possible link appears to
exist between rapid metabolizers and lung cancer.
13 Several P450s are also
involved in steroid biosynthesis and metabolism. As mentioned previously,
some researchers suggest that a general increase in estrogenic activity may be
responsible for the observed increases in breast and testicular cancers.
6.8 REFERENCES
1. Kappas, A. and Alvares, A.P., How the liver metabolizes foreign substances,
Sci. Am., 232, 60, 1975.
2. Wislocki, P.G., Miwa, M.T. and Yu, A.Y.H., Reactions catalyzed by the
cytochrome P-450 system, in Jakoby, W.B., Ed., Enzymatic Basis of
Detoxication, Vol. 1, Academic Press, New York, 1980, p.135.
3. Reynolds, E.S., Environmental aspects of injury and disease: Liver and bile
ducts, Environ. Health Perspect., 20, 1, 1977.
4. Reynolds, E. S. and Moslen, M. T., Environmental liver injury: Halogenated
hydrocarbons, in Farber, E. and Fisher, M.F., Eds., Toxic Injury of the Liver,
Marcel Dekker, New York, 1980, p.541.
5. Van Bladeren, P.J. et al., The role of glutathione conjugation in the
mutagenicity of 1,2-dibromoethane, Biochem. Pharmacol., 29, 2975, 1980.
Environmental Toxicology
[16:54 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-006.3d]
Ref: 4365 MING-HO YU Chap-006 Page: 96 85-98
chemicals or certain drugs. For instance, CYP1A1 and CYP1A2 are induced in
smokers, while CYP2E1 is induced by ethanol and isoniazid, etc. Many studies
have shown increases in MFO enzymes from organisms following exposure to
xenobiotics. Such inducers of cytochrome P450 increase the rate of xenobiotic
biotransformation. As a consequence of this phenomenon, it would be
expected that there could be increases in the activation of procarcinogens to
DNA-reactive metabolites, leading to increased tumor formation. However, it
is not clear whether this is indeed the case in humans. In many instances, P450
induction does not necessarily enhance the biotransformation of the inducer.
6
Fish from waters that receive pulp-mill effluents have been shown to
respond to the effluents with increases in hepatic MFO activity, particularly
that of EROD.
11 In a recent study, a compound isolated from a bleached-kraft
mill effluent (tentatively identified as a chlorinated pterostilbene) was shown to
be capable of causing MFO induction in rainbow trout and in a hepatocyte cell
line.
12
6.7.2 GENETIC POLYMORPHISMS
Another characteristic feature of cytochrome P450s is the occurrence of genetic
polymorphism, resulting in enzyme levels and activities varying greatly between
different individuals. Genetic polymorphism includes defects in CYP2D6 and
variations in CYP1A2 activities. For example, three phenotypes are found in
CYP1A2: slow, medium, and rapid metabolizers. Research shows that this
phenomenon is related to susceptibility of individuals to certain types of cancer
– for example, increased bladder and colorectal cancer susceptibility for rapid
1A2 populations. Similarly, marked ethnic differences exist with CYP2D6, and
usually 1 to 10% of the population are poor metabolizers who may develop
less-aggressive forms of bladder cancer. Conversely, a possible link appears to
exist between rapid metabolizers and lung cancer.
13 Several P450s are also
involved in steroid biosynthesis and metabolism. As mentioned previously,
some researchers suggest that a general increase in estrogenic activity may be
responsible for the observed increases in breast and testicular cancers.
6.8 REFERENCES
1. Kappas, A. and Alvares, A.P., How the liver metabolizes foreign substances,
Sci. Am., 232, 60, 1975.
2. Wislocki, P.G., Miwa, M.T. and Yu, A.Y.H., Reactions catalyzed by the
cytochrome P-450 system, in Jakoby, W.B., Ed., Enzymatic Basis of
Detoxication, Vol. 1, Academic Press, New York, 1980, p.135.
3. Reynolds, E.S., Environmental aspects of injury and disease: Liver and bile
ducts, Environ. Health Perspect., 20, 1, 1977.
4. Reynolds, E. S. and Moslen, M. T., Environmental liver injury: Halogenated
hydrocarbons, in Farber, E. and Fisher, M.F., Eds., Toxic Injury of the Liver,
Marcel Dekker, New York, 1980, p.541.
5. Van Bladeren, P.J. et al., The role of glutathione conjugation in the
mutagenicity of 1,2-dibromoethane, Biochem. Pharmacol., 29, 2975, 1980.