Mechanism of chemical carcinogenesis: an alternative hypothesis.
Ultimate carcinogens are usually very reactive electrophilic species and therefore of transient existence in the cell. Both because of the biological reactivity and the inherent danger in their reaction with DNA, direct interaction with the latter is prevented, especially in higher mammalian cells, by various cell defence mechanisms and, lastly, by a nuclear membrane monitoring system. Hence, reaction of chemical carcinogen with nuclear DNA is possible only when the cell is overwhelmed leading to cell death, or following a temporary breach of the nuclear membrane control points, but the DNA damage in the latter is totally reparable. Both situations are therefore of no consequence to chemical carcinogenesis. Instead, the excess electrical charge created by the physical presence of the electrophilic carcinogens is hypothesized to predispose the cell to irreversible genetic changes like cellular oncogene activation, or uncontrolled cell proliferation common to cancerous cells. These effects would be catalyzed by a Na+-H+ exchange-mediated intracellular alkalinization resulting from the cell's attempt to restore electrical neutrality by elevating the Na(+)-pump activity, fuelled by an increased Na+/H+ antiport.
Nwankwo
J O
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Kenneth Norris Cancer Hospital and Research Institute, USC School of Medicine, Los Angeles 90033.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D002352:Carrier Proteins / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D009369:Neoplasms / Q000139:chemically induced*; D014176:Protein Biosynthesis; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers
D002273:Carcinogens; D002352:Carrier Proteins; D017923:Sodium-Hydrogen Exchangers; D004247:DNA; D012964:Sodium