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Association between Diet and Age-related DNA Modifications (I-Compounds) in Rat Liver and Kidney¹

Division of Toxicology, Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030

Mammalian tissue DNA has recently been found, by ³²P-postlabeling, to contain complex profiles of age-dependent and tissue-specific bulky carcinogen adduct-like modifications, which have been termed I-compounds since they appeared to arise indigenously, in the absence of exposure to exogenous carcinogens. I-compounds are presumably formed by reaction of metabolically produced, as yet unidentified, electrophiles with DNA. In order to shed light on the origin of I-compounds, we have examined whether diet affects the levels and profiles of I-compounds. Weanling female Sprague-Dawley rats were provided with either one of three natural ingredient diets (rodent chows) or a purified diet (AIN-76A) for up to 6 months. Liver and kidney DNAs were analyzed after 0, 3, and 6 months of feeding, by a nuclease P1-enhanced ³²P-postlabeling assay. Rats fed natural ingredient diets showed a greater complexity and 2.5–6.4-fold higher levels of I-compounds in the DNA of both tissues than rats fed purified diet. In addition, less marked qualitative and quantitative differences were noted among rats fed different chow diets. Three classes of I-compounds were identified: class A, I-spots common to both kinds of diet; class B, chow-specific spots; and class C, AIN-76A-specific spots. Liver and kidney shared some I-compounds, mostly belonging to class A, but there were also tissue-specific spots. These observations indicate a novel intimate link between diet and DNA modifications and are consistent with the hypothesis that the formation of I-compounds proceeds via normal metabolism of nutrients and other natural dietary components, leading to the production of small amounts of DNA-reactive electrophiles. Because of their DNA adduct-like character, I-compounds may play a critical role at the interface between nutrition and cancer.

¹ This work was supported by USPHS Grants R37 CA 32157 awarded by the National Cancer Institute and R01 AG 07750 awarded by the National Institute on Aging.

² To whom requests for reprints should be addressed, at Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.

Received 12/27/89. Revised 3/15/90.

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