Oncology General Principles Continued
An important group of chemicals that have been implicated in human cancer are polycyclic aromatic hydrocarbon (PAH).
Most of these chemicals tend to be produced during combustion and other processes unintentionally; however, some are produced commercially.
These examples include:
Of these industrial products, the most important is probably naphthalene.
These agents are typically not chemically synthesized for industrial use but are isolated from coal processing products, mainly from coal-tar.
Naphthalene may be occasionally isolated from pyrolysis residue oils, petroleum-derived fractions and olefin fractions.42
Historically, polycyclic aromatic hydrocarbons had been correlated with certain, high incidence cancers within particular occupational subpopulations.
For instance, increase risk of scrotal cancer among chimney sweeps is likely associated with exposure to select and tar.
Application of coal tar to skin a test animals led to the identification of the chemical constituents responsible for malignancy.
These constituents were the polycyclic aromatic hydrocarbons (PAHs).
Increased likelihood of lung cancer has also been associated with occupational exposure to PAHs; occupations associated with increased worker risk include roofers and pavers, coke oven workers, some workers involved in steel/iron manufacturing as well as those involved in aluminum production.36
Metabolic, biochemical pathways for PAHs and benzo[a]pyrene have been identified (see figure below).
Note the initial step in benzo[a]pyrene metabolism which involves epoxidation of an aromatic double bond by one of the cytochrome P450 monooxygenases (CYP1A1).
Epoxide-benzo[a]pyrene intermediates can lead to phenol or glutathione conjugate formation.
Another possibility is additional oxidation by epoxide hydrolase to form dihydrodiol-benzo[a]pyrene.
An additional, second, oxidation step can lead to a very reactive 7, 8-dihydrodiol-9,10-epoxide benzo[a]pyrene.
In human lung and colon tissue benzo[a]pyrene may be metabolized to the likely carcinogen 7, 8-dihydro-7,8-dihydrobenzo[a]pyrene.
These results were obtained using tissue culture techniques.
Benzo[a]pyrene administered to other test animals orally resulted in benzo[a]pyrene-DNA adduct formation in a number of tissues.36
Aromatic amines have been implicated in bladder cancer etiology.
Initial observations of increased incidence of bladder cancer in dye industry workers were reported over 100 years ago. 1-naphthylamine, 2-naphthylamine, and benzidine (arylamines) as well as mixed-dyes have been implicated.
Aromatic amines are metabolized by a process involving acetylation.
The enzyme that catalyzes this reaction is N-acetyltransferase.
Genetic polymorphism results in enzyme form variants that exhibit different acetylation rates.
Expression of one NAT2 (N-acetyltransferases 2) gene form is associated with relatively slower acetylation rates; moreover, these lower rates may predispose to a higher incidence of aromatic amine-induced bladder cancer.36
Bladder cancer involves transformation of normal urothelial cells to malignant cells with possible subsequent development of metastatic disease.
The mechanistic foundation of malignant transformation as a result of exposure to arylamines, such as 1-naphthylamine, or aromatic amines, such as 4-aminobiphenyl, is based on formation of DNA adducts.
These modifications in DNA is influenced by activity of certain liver enzymes either involved in phase I (cytochrome P450 system metabolism) or phase II metabolism (N-acetyltransferase 2, i.e. NAT2) and glutathione-S-transferase M1 (GSTM1).
One particular cytochrome P450 isozyme especially important in this process appears to be CYP1A2, which is an inducible enzyme catalyzing aromatic amine demethylation with attendant increase in DNA adduct formation.
NAT2 catalyzes the formation of acetylated products which tend to be relatively non-reactive; therefore, these acetylation reactions appear to reduce DNA adduct formation.45
Benzene exposure may result in increased nonlymphocytic leukemia and lymphoma.
This risk may be most likely observed in workers who are exposed to solvents associated with rubber film and rubber coating production.
The underlying mechanism for benzene-induced leukemogenicity remains to be elucidated but may involve metabolic change, growth factor dysregulations, oxidative stress, DNA damage, cell cycle dysregulation and alterations in apoptotic mechanisms.
Benzene induced hematotoxicty has been suggested to be associated with abnormalities in the p53 transcription factor.
p53 activity is regulated by control of p53 protein levels.
p53 binds to an oncogene product mdm2 and the complex is transported from the nucleus for proteolytic degradation; therefore, nuclear p53 levels can be regulated by the extent of complex formation and translocation.
Phosphorylation of p53 as well as mdm2, a response to noxious stimulation, changes the equilibrium between p53, mdm2 and the complex p53-mdm2 in a way that favors free p53.
As a result, under some pathological circumstances, increased p53 levels predispose the cell to apoptosis or cell cycle arrest.
If a mutagenic event occurs that compromises p53 regulation, one possibility is that reduced p53 efficacy results in reduced apoptosis and reduced cell cycle arrest.
Acquired p53 mutation is likely the most common genetic change observed in human cancer.36,48,49
Aflatoxin is produced by certain fungal strains (Aspergillus flavus and A. parasiticus).
Aflatoxin B is a hepatotoxin which under some circumstances can be associated with an increased and high liver cancer rate.
Possibly a co-carcinogenic relationship exists between aflatoxin and hepatitis B virus (HBV).
Following aflatoxin exposure, at least in amounts in excess of 10-100 µg/day, aflatoxin metabolites as well as aflatoxin-DNA adducts can be assayed in urine.
Aflatoxin may exert its hepatocellular carcinogenic activity through p53 dysregulation, as suggested below:
Cytochrome p450 cycle (diagram by Matthew Segall, 1997)
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