Cancer procarcinogens

Shimada, T., Iwasaki, M., Martin, M.V. Guengerich, F.P. (1989) Human liver microsomal cytochrome P-450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA 1535/pSK1002. Cancer Res., 49, 3218-3228... 

Procarcinogen 1. An irreversible process that does not necessarily lead to cancer... 

Cancer Probably There is good evidence for substantial involvement of radicals in the activation of certain procarcinogens and in promotion. 

Branch RA, Chem HD, Adedoyin A, et al. The procarcinogen hypothesis for bladder cancer activities of individual drug metabolizing enzymes as risk factors. Pharmacogenetics 1995 5 S97-S102. 

A second example of sulfate bioactivation derives from the observed carcinogenicity of aromatic amineS/ such as those derived from coal tar (44). The polycyclic aromatic amines are N-hydroxylated by CYPs and then sulfated to form unstable N-O-sulfates that decompose and produce reactive nitrenium ion intermediates/ which form DNA and protein adducts. One environmental/genetic hypothesis of colon cancer etiology involves the interaction between dietary aromatic amines and the polymorphic expression of the appropriate STs for their activation to procarcinogenic reactive intermediates (44/ 45). 

Benzidine is metabolized to highly toxic, reactive metabolites, such as N-hydroxyarylamides and N-hydroxyarylamines, which act as procarcinogens and are more mutagenic than parent compounds. The metabolites act as DNA adducts and bind to cell receptors. The metabolites on conjugation with sulfuric, acetic, and glucuronic acids form ultimate carcinogens. Acetylated benzidine metabolites such as N-acetoxyarylamines are known to cause bladder cancer in dye industry workers. 

Knowles and Milner, 2000). Furthermore, these compounds are thought to be involved in the inhibition of certain cytochrome P-450 enzyme-dependent bioactivations of procarcinogens and protoxicants (Brady et al., 1991), as well as to increase levels of glutathione-S-transferase (GST), an enzyme of particular importance in the detoxification of xenobiotics in the body (Wilce and Parker, 1994). Most recently, the ability of various plants and plant extracts to influence apoptosis, or programmed cell death, in cancerous cells in an attempt to arrest their proliferation, has been the topic of much research. Allicin has been shown to induce apoptosis in a variety of cell lines, including human hepatocellular carcinoma cells (KIM-1) and human lymphoid leukemia (MOLT-4B) cells (Thatte et al., 2000). 

Shimada T, El-Bayoumy K, Upadhyaya P, et al. 1997. Inhibition of human cytochrome P450-catalyzed oxidations of xenobiotics and procarcinogens by synthetic organoselenium compounds. Cancer Res 57 4757-4764. 

There are numerous cellular targets with which carcinogens may interact, but attention has focused on nucleic acids, particularly DNA. It is indisputable that many carcinogens are electrophiles (direct acting or procarcinogens) which react covalently with DNA as well as other cellular macromolecules. The fact that the neoplastic transformation is heritable implies that an alteration in DNA may have occurred, and the observation that many cancers have altered gene expression and chromosomal abnormalities also supports the central role of DNA as the target. 

S.S. Hecht, F.P. Guengerich et al. (1996). Activation of chemically diverse procarcinogens by human cytochrome P450 IBl. Cancer Res. 56,2979-2984. 

A suggestion has been made that those with EM phenotypes may be more prone than those with PM phenotypes to develop cancers, because they are better able to activate procarcinogens. Such interindividual variations may have a major influence in determining the risk of cancer. The activity of a particular CYP450 isotorm may be a rationale tor predicting the individual risk from exposure to carcinogenic compounds. 

If activation of procarcinogens to electrophilic metabolites is enhanced, the expectable result is an increase in the number of carcinogenically active molecules capable of initiating cancer. Conversely, as deactivation or detoxification increases, one would expect lesser amounts of potentially carcinogenic metabolites available to initiate cancer induction. 

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