Effects of a single dose of the cytochrome P450 inducer, beta-naphthoflavone, on hepatic and renal covalent DNA modifications (I-compounds).
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 CYP1A1 inducer, beta-naphthoflavone (BNF) (80 mg/kg), in corn 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 methoxyresorufin-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 CYP1A1 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.
Moorthy
B
B
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
Sriram
P
P
Randerath
K
K
D000818:Animals; D001571:Benzoflavones / Q000633:toxicity*; D003314:Corn Oil / Q000008:administration & dosage / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010088:Oxidoreductases / Q000096:biosynthesis*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D018736:DNA Adducts; D019324:beta-Naphthoflavone; D003314:Corn Oil; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019363:Cytochrome P-450 CYP1A1