BIOCHEMISTRY OF CARCINOGENESIS

Cancer is a condition characterized by the uncontrolled replication and growth of the body’s own cells (somatic cells).  It is now generally believed that many – and perhaps most – cancers are started by the action of synthetic and naturrally occuring chemicals (in some cases viruses cause cancer).  The role xenobiotic chemicals in causing cancer is called chemical carcinogenesis.  It is often regarded as the single most important facet of toxicology and clearly the one that receives the most publicity.

Despite large expenditures of time and money on the subject, the biochemical bases of chemical carcinogenesis are not well understood.  The overall processes for the induction of cancer may be quite complex, involving numerous steps.  It is generally recognized that there are two major steps : an initiation stage followed by a promotional stage.  Chemical carcinogens are often mutagens and it is believed that in many cases cancerous cells result from mutations of normal cells exposed to carcinogens.  This implies that that chemical carcinogens alter DNA in a manner such that an “outlaw cell” is formed that continues to replicate itself and form cancerous tissue.

Chemical carcinogens usually have the ability to form covalent bonds with macromolecular life molecules, especially DNA.  Prominent among these are the alkylating agents which attach alkyl groups – such as methyl (CH₃) or ethyl (C₂H₅) – to DNA.  A similar type of compound, arylating agents, act to attach aryl to DNA.  The alkyl and aryl groups become attached to N and O atoms in the nitrogenous bases that compose DNA.  This leads to alteration in the DNA and it can result in the growth and replication of neoplastic (cancerous) cells.

In order for them to cause cancer, most most cancer-causing substances require metabolic activation and are called precarcinogens or procarcinogens.  The metabolic species actually responsible for carcinogenesis, usually by its interaction with DNA, is termed an ultimate carcinogen.  Some species that are intermediate metabolites between precarcinogens and ultimate carcinogens are called proximate carcinogens.  Carcinogens that do not require biochemical activation are categorized as primary or direct-acting carcinogens.

In some cases chemicals are known to be carcinogens from epidemiological studies of exposed humans.  Animals are used to test for carcinogenicity, and the results can be extrapolated with some uncertainty to humans.  The most broadly applicable test for potential carcinogens is the Bruce Ames procedure, which actually reveals mutagenicity.  The principle of this method is the reversion of mutant histidine-requiring Salmonella bacteria back to a form that can synthesize their own histidine.  The bacteria are inoculated onto a medium that does not contain histidine, and those that mutate back to a form that can synthesize histidine establish colonies which are assayed on the growth medium, thereby providing both a qualitative and quantitative indication of mutagenicity.  The test chemicals are mixed with homogenized liver tissue to simulate the body’s alteration of chemicals (conversion of procarcinogens to ultimate carcinogens).  Up to 90% correlation has been found between mutagenesis on this test and known carcinogenicity of test chemicals.

for further informations :

Manahan, Stanley E.; Toxicological Chemistry;