3-Methylcholanthrene-inducible liver cytochrome(s) P450 in female Sprague-Dawley rats: possible link between P450 turnover and formation of DNA adducts and I-compounds.
The hepatic cytochrome P450s are mixed-function oxidases which metabolize a wide variety of xenobiotics and endobiotics, and also bioactivate carcinogens such as 3-methyl-cholanthrene (MC) to reactive metabolites capable of forming DNA adducts. To investigate possible relationships between cytochrome P450 induction and covalent DNA modifications (adducts and I-compounds), female Sprague-Dawley rats were i.p. treated with MC (25 mg/kg) in corn oil (CO), once daily for 4 days. Controls received CO only. Animals were euthanized at 1, 8, 15, 28 and 45 days after the last MC treatment, and liver microsomal cytochrome P450, ethoxycoumarin O-deethylase (ECD) and ethoxyresorufin O-deethylase (EROD) activities were determined. Liver DNA adducts and I-compounds were analyzed by 32P-postlabeling. A significant induction of the levels of P450, ECD and EROD activities was noted in MC-treated rats, and elevated enzyme levels persisted for about 6 weeks after cessation of MC administration. Linear decay of total P450, ECD and EROD activities as a function of time was observed. MC induced 11 DNA adducts in liver, which were resolved by thin-layer chromatography (TLC) and persisted at high levels throughout the study. On the other hand, MC elicited a significant depletion of both non-polar and polar I-compounds (age-dependent DNA modifications detectable by 32P-postlabeling in rodent tissues without known exposure to carcinogens). Level of most I-compounds returned to normal at 45 days, and this paralleled the return of P450-related activities to normal. These results suggest a possible link between P450 turnover, DNA adduct formation, and I-compound depletion.
Moorthy
B
B
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Chen
S
S
Li
D
D
Randerath
K
K
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004790:Enzyme Induction; D005260:Female; D007700:Kinetics; D008748:Methylcholanthrene / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013997:Time Factors
D008748:Methylcholanthrene; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D015660:7-Alkoxycoumarin O-Dealkylase; D019363:Cytochrome P-450 CYP1A1