Effects of a single dose of the cytochrome P450 inducer, β-naphthoflavone, on hepatic and renal covalent DNA modifications (I-compounds)

• Published in: Toxicology (Amsterdam) 1995-12, Vol.104 (1), p.165-177
• Main Authors: Moorthy, Bhagavatula, Sriram, Padmavathi, Randerath, Kurt
• Format: Article
• Language: English
• Subjects: 32P-postlabeling; Animals; Benzoflavones - toxicity; beta-Naphthoflavone; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Corn Oil - administration & dosage; Corn Oil - toxicity; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System - biosynthesis; DNA - biosynthesis; DNA - drug effects; DNA - metabolism; DNA Adducts - metabolism; DNA modifications; Dose-Response Relationship, Drug; Enzyme Induction - drug effects; Female; Gene Expression Regulation - drug effects; I-compounds; Kidney - drug effects; Kidney - enzymology; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Oxidoreductases - biosynthesis; P450 induction in rats; Random Allocation; Rats; Rats, Sprague-Dawley; Tumors; β-Naphthoflavone
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/0300-483X(95)03181-E

I-compounds are age-dependent covalent DNA modifications, which occur in rodent tissues without known carcinogen exposure. A number of studies from our laboratory indicate that I-compounds may serve as biomarkers of carcinogenesis. Recently, we demonstrated significant lowering of liver I-compound levels in rats that were exposed to different cytochrome P450 inducers. In order to gain further mechanistic insights into the possible relationship between P450 induction and I-compound reduction, female Sprague-Dawley rats were administered a single dose of the CYP1 Al inducer, β-naphthoflavone (BNF) (80 mg/kg), in com oil (CO) (2 ml/kg) or CO only (2 ml/kg) as vehicle control. Liver and kidney microsomal P450 contents and P450-related enzyme activities and DNA I-compounds were determined at 4, 24, and 48 h after treatment. Liver and kidney I-compounds were analyzed by nuclease P1-enhanced 32P-postlabeling. DNA synthesis was determined by measuring [ 3H]methylthymidine incorporation. Liver and kidney microsomal P450 contents were elevated by BNF at 24 and 48 h. Ethoxyresorufin-O-deethylase (EROD) and methoxyresorufm- O-demethylase (MROD) were significantly elevated at all time points, with the former displaying a much higher extent of induction. BNF treatment resulted in significant diminution of the levels of several individual and total I-compounds in liver at 48 h, but few effects were seen at the earlier time-points. Kidney I-compounds were also markedly affected by BNF at 48 h, albeit to a lesser extent than in liver. In both tissues, P450 induction preceded I-compound reduction. Taken together, the results of this investigation demonstrate significant diminution of I-compound levels by a single dose of BNF, a CYP1 A1 inducer, in a time-dependent manner, suggesting the participation of a specific biochemical process, possibly involving CYP1A1, in the metabolic regulation of these endogenous DNA adducts.