The human diet contains a great variety of natural mutagens and carcinogens, as well as many natural antimutagens and anticarcinogens. Many of these mutagens and carcinogens may act through the generation of oxygen radicals. Oxygen radicals may also play a major role as endogenous initiators of degenerative processes, such as DNA damage and mutation (and promotion), that may be related to cancer, heart disease, and aging. Dietary intake of natural antioxidants could be an important aspect of the body’s defense mechanism against these agents. Many antioxidants are being identified as anticarcinogens. Characterizing and optimizing such defense systems may be an important part of a strategy of minimizing cancer and other age-related diseases.

https://science.sciencemag.org/content/sci/221/4617/1256.full.pdf

Dietary carcinogens and anticarcinogens Oxygen radicals and degenerative diseases

Review of the biology of quercetin and related bioflavonoids

Dietary agents in cancer prevention: flavonoids and isoflavonoids.

This review compiles and evaluates existing scientific information on the use, limitations, and procedural considerations for EROD activity (a catalytic measurement of cytochrome P4501A induction) ...

Ethoxyresorufin-O-deethylase (EROD) activity in fish as a biomarker of chemical exposure.

The epidemiologic literature on the relationship between vegetable and fruit consumption and human cancer at a variety of sites was reviewed systematically in Part I.1 It was concluded that consumption of higher levels of vegetables and fruit is associated consistently, although not universally, with a reduced risk of cancer at most sites, and particularly with epithelial cancers of the alimentary and respiratory tracts. Possible mechanisms by which vegetable and fruit intake might alter risk of cancer are addressed here. A large number of potentially anticarcinogenic agents are found in these food sources, including carotenoids, vitamins C and E, selenium, dietary fiber, dithiolthiones, glucosinolates and indoles, isothiocyanates, flavonoids, phenols, protease inhibitors, plant sterols, allium compounds, and limonene. These agents have both complementary and overlapping mechanisms of action, including the induction of detoxification enzymes, inhibition of nitrosamine formation, provision of substrate for formation of antineoplastic agents, dilution and binding of carcinogens in the digestive tract, alteration of hormone metabolism, antioxidant effects, and others. It appears extremely unlikely that any one substance is responsible for all the associations seen. Possible adverse effects of vegetable and fruit consumption are also examined. One way to consider the relationships reviewed here is to hypothesize that humans are adapted to a high intake of plant foods that supply substances crucial to the maintenance of the organism, but only some of which are currently called ‘essential nutrients.’ Cancer may be the result of reducing the level of intake of foods that are metabolically necessary—it may be a disease of maladaptation.

Vegetables, fruit, and cancer. II. Mechanisms.

Several compounds such as flavonoids, selenium, antioxidants and retinoids reportedly reduce the induction of cancer in experimental animals, and some have been suggested to function by affecting the mixed-function oxidase (MFO) system. The following compounds: 50 and 500 p.p.m. beta-naphthoflavone (BNF), 1000 p.p.m. flavone, 1000 p.p.m. of a tangeretin - nobilitin mixture, 1000 p.p.m. beta- ionone , 1000 p.p.m. indole-3-carbinol ( I3C ) and 2000 p.p.m. quercetin were examined for protection against aflatoxin B1 (AFB1) hepatocarcinogenesis, induction of the MFO system and metabolism of AFB1 in rainbow trout. These compounds were fed to fingerling rainbow trout for 8 weeks. At that time the activity of several MFO enzymes and cytochrome P450 content were measured and the trout were exposed for 2 weeks to 20 p.p.b. AFB1 in the same diets. After feeding the test diets without AFB1 for another 6 weeks and basal diet for another 52 weeks, the tumor incidence was determined. The effect of BNF and I3C on in vivo binding of AFB1 to DNA was also measured in separate groups of trout. BNF induced the trout MFO system in a dose-dependent manner, tangeretin - nobilitin was less effective and I3C did not induce. BNF showed significant alterations in the metabolism of AFB1 to aflatoxicol and aflatoxin M1 using cell fractions from pretreated fish. None of the other compounds, including I3C showed such an effect. Despite the apparent lack of in vitro effect of I3C , both BNF and I3C reduced AFB1 - DNA binding in vivo. I3C and BNF provided marked protection against AFB1-induced hepatocarcinogenesis, while the other compounds were less effective. The 58 weeks tumor incidences were 4% for 1000 p.p.m. I3C , 6% for 500 p.p.m. BNF and 18% for 50 p.p.m. BNF, compared to 38% for the AFB1-positive control. These data demonstrate that gross induction of the MFO system was not necessarily required for alterations in DNA adduct formation in vivo or protection against AFB1 carcinogenesis. Both BNF and I3C provided marked protection but only BNF induced the MFO system.

Inhibition of aflatoxin B1 carcinogenesis in rainbow trout by flavone and indole compounds.

Indole-3-carbinol (I3C), a natural constituent of cruciferous vegetables, is an inhibitor in several experimental animal models of carcinogenesis by polynuclear aromatic hydrocarbons or aflatoxin B1 (AFB1) when administered prior to or during carcinogen exposure For assessment of the postinitiation effects of I3C, rainbow trout were exposed to dietary I3C in two different protocols--before and during AFB1 exposure or after AFB1 exposure only Preinitiation exposure to I3C reduced AFB1-initiated hepatocellular carcinomas in trout as previously reported, but post-initiation I3C exposure strongly enhanced the tumor incidence above the positive AFB1 control These results reveal the need for additional research to elucidate the overall effect of I3C on chemical carcinogenesis

Enhancement of carcinogenesis by the natural anticarcinogen indole-3-carbinol.

Systematic design of replacement chemicals with reduced toxicities will require knowledge of mechanisms of action of parent compounds, especially in species which occupy the environment of most likely exposure. For aquatic systems, the rainbow trout has proven a valuable model for studying mechanisms of carcinogenicity. By comparison, small aquarium species show great potential as in situ field monitors of aquatic contamination by toxic chemicals but are less developed for mechanism studies. Fish species, especially rainbow trout, have also proven useful alternatives to traditional rodent models for comparative studies on mechanisms of action of nonaquatic carcinogens. These kinds of comparative studies form an essential basis for extrapolation of animal studies to man. Carcinogenicity testing of individual compounds and their replacements can provide only limited information on the expected impact of such chemicals on natural populations, since these populations are unavoidably exposed to potent modulators of the carcinogenic response. Hence any program which aims at redesign of commercial chemicals with reduced toxicities must have as a prior aim the full understanding of the mechanisms of joint carcinogen-inhibitor-promotor interactions. Because of their high sensitivity, low cost per individual, and low background tumor incidences, fish models such as the rainbow trout may be the only vertebrate models in which it is economically practical to initiate such complex studies.

The sensitivity of rainbow trout and other fish to carcinogens.

A modification of the Ames assay using rainbow trout (Salmo gairdneri) liver postmitochondrial fraction (PMF) was developed to investigate the relative mutagenic potential of a series of aflatoxins (AFs). Preliminary experiments revealed that the 20000 x g (S20) liver fraction contained a higher metabolic activity than either the S9 or S30 fractions, and that 5 mg of S20 protein/plate gave the highest mutagenic response. A 9-24 h preincubation period at 25 degrees C was also required. The results from comparative mutagenicity experiments showed the following relative potencies: AFB1 greater than AFL greater than AFG1 greater than AFM1 greater than AFB2 greater than AFP1 greater than AFQ1. The relative potencies observed with this in vitro system qualitatively correlated with the in vivo carcinogenic activity seen in trout, indicating that this assay is of value in predicting the carcinogenic potential of mycotoxins in this species.

Comparative Mutagenicity of Aflatoxins Using a Salmonella/Trout Hepatic Enzyme Activation System

Aflatoxicol (AFL), a major metabolite of aflatoxin B1 (AFB1) in the Mt. Shasta rainbow trout (Salmo gairdneri), was found to produce hepatocellular carcinoma in trout. It was administered in a casein diet to duplicate groups of 120 fingering trout. In the same manner, additional duplicate groups received one of the following: no toxicant; AFB1; the diastereomer of AFL (AFL'); cyclopropenoid fatty acids (CPFA); and CPFA plus AFB1, AFL, and AFL'. Eight months after the initiation of the study, the following incidences of carcinoma were observed: control (0%); 20 ppb AFB1 (56%); 29 ppb AFL (26%); 61 ppb AFL' (0%); 50 ppm CPFA (3%); 20 ppb AFB1 plus 50 ppm CPFA (96%); 29 ppb AFL plus 50 ppm CPFA (94%); and 61 ppb AFL' plus 50 ppm CPFA (55%), showing both the carcinogenicity of AFL and the synergistic effects of CPFA. Twelve-month incidences were correspondingly higher in all cases. Aflatoxin M1, another metabolite of AFB1 in rainbow trout, was reported previously to be carcinogenic in trout. These results support the hypothesis that metabolism in rainbow trout does not effectively detoxify AFB1, but rather the formation of AFL extends the carcinogenicity of AFB1 and may contribute to the high sensitivity of rainbow trout to AFB.

https://cancerres.aacrjournals.org/content/canres/41/3/1011.full.pdf

J.E. Nixon

Papers

Inhibition of aflatoxin B1 carcinogenesis in rainbow trout by flavone and indole compounds.

Enhancement of carcinogenesis by the natural anticarcinogen indole-3-carbinol.

The sensitivity of rainbow trout and other fish to carcinogens.

Comparative Mutagenicity of Aflatoxins Using a Salmonella/Trout Hepatic Enzyme Activation System

Aflatoxicol-induced Hepatocellular Carcinoma in Rainbow Trout (Salmo gairdneri) and the Synergistic Effects of Cyclopropenoid Fatty Acids