Oxidants and mitogenesis as causes of mutation and cancer: the influence of diet.
A very high level oxidative damage to DNA occurs during normal metabolism. In each rat cell, the steady-state level of this damage is estimated to be about 10(6) oxidative adducts, and about 10(5) new adducts are formed daily. This endogenous DNA damage appears to be a major contributor to cancer and aging. The oxidative damage rate in mammalian species with a high metabolic rate, short life span, and high age-specific cancer rate such as in rats is much higher than the rate in humans, long-lived mammals with a lower metabolic rate, and a lower age-specific cancer rate. It is argued that deficiency of micronutrients, that protect against oxidative DNA damage, is a major contributor to human cancer. Epidemiological studies, a large body of experimental evidence, and theoretical work on the mechanisms of carcinogenesis point to mitogenesis as a major contributor to cancer. Dividing cells, compared to nondividing cells, are at an increased risk for mutations due to: 1.) conversion of DNA adducts to mutations; 2.) chance of mitotic recombination, gene conversion, and nondisjunction; and, 3.) increased exposure of DNA to mutagens. Mitogenesis also increases the probability of gene amplification and loss of 5-methylcytosine. Dietary interventions that lower mitogenesis, such as calorie restriction, decrease cancer incidence.
Shigenaga
M K
MK
Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720.
Ames
B N
BN
D000375:Aging; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004032:Diet; D002149:Energy Intake; D006801:Humans; D008934:Mitogens / Q000633:toxicity*; D009153:Mutagens / Q000633:toxicity*; D009369:Neoplasms / Q000139:chemically induced / Q000209:etiology*; D016877:Oxidants / Q000633:toxicity*
D002273:Carcinogens; D008934:Mitogens; D009153:Mutagens; D016877:Oxidants