Procarcinogens, Cytochrome

Figure 4. Proposed scheme for Cytochrome P-450 mediated metabolism (inactivation and activation) of procarcinogens (e.g. PAHs).

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... 

Code EL, Crespi CL, Permian BW, Gonzalez FJ, Chang TK, Waxman DJ. Human cytochrome P4502B6 interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metab Dispos 1997 25 985-993. 

They reduce the activation of many procarcinogens to the active proximate carcinogen by lowering the activity of microsomal cytochrome P450 enzymes. 

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). 

The conclusion of the study was that interindividual variations in the amount of human cytochrome 2A6 and 2E1 could contribute to the susceptibility of environmental procarcinogens including those derived from tobacco smoke. Cytochromes P-450 largely bioactivate nicotine and nicotine-related nitrosoamines to electrophilic materials. Presumably, the balance between bioactivating enzyme activity and detoxicating enzyme activity is important in determining the overall susceptibilities of humans to exposure to chemicals. Below, the properties of several additional enzymes in nicotine detoxication are described. 

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. 

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

F.P. Guengerieh, and K. Inoue (2001). Metabolic activation of polycyclic aromatic hydrocarbons and their dihydrodiol derivatives and other procarcinogens by cytochrome P450 lAl and IBl allelic variants and other human cytochrome P450 enzymes in Salmonella typhimurium NM2009. Drug Metab. Dispos. 29, 1176-1182. 

Table 10.4. Some Procarcinogens and Other Toxins Activated by Human Cytochrome P450s CYP1A1 CYP1A2 CYP2E1 CYP3A4...

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