Abstract
We reported earlier that 3-methylcholanthrene (MC) persistently induces hepatic ethoxyresorufinO-deethylase activities (CYP1A1) in rats for up to 45 days. In this investigation, we tested the hypotheses that persistent expression of CYP1A1 activities is paralleled by sustained induction of CYP1A1/CYP1A2 apoproteins and their mRNAs and that this phenomenon is mediated by mechanisms other than retention of MC in the rat. Rats were given MC (93 μmol/kg) i.p., once daily for 4 days, and CYP1A1/1A2 parameters were measured in liver at selected time points. MC-elicited increases in CYP1A1/1A2 activities, apoprotein contents, and mRNA levels were sustained for several weeks after the last dose of MC treatment. MC also caused long-term induction of CYP1A1 in lungs and mammary glands. Rats treated with [3H]MC once daily for 4 days excreted 92.3% of the administered radioactivity in feces and urine by day 15. The intrahepatic concentration of MC at the 15-day time point was 270 pmol/g. Dose-response studies showed that administration of MC (2 μmol/kg), which produced an intrahepatic concentration of 271 pmol/g after 24 h, did not induce CYP1A1/1A2 activities, strongly suggesting that the sustained induction of CYP1A1/1A2 was not due to retention of the parent MC in the body. Electrophoretic mobility shift assays revealed that persistent CYP1A1 induction by MC involved Ah receptor-independent mechanisms. In conclusion, our results support the hypothesis that persistent expression of CYP1A1/1A2 by MC is mediated by mechanisms independent of the retention of the parent carcinogen.
Footnotes
-
Send reprint requests to: Dr. Bhagavatula Moorthy, Ph.D., Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail: bmoorthy{at}neo.bcm.tmc.edu
-
↵1 This work was supported in part by U.S. Public Health Service (USPHS) Grant ES09132 from the National Institute of Environmental Health Sciences and a grant-in-aid from the American Heart Association (Texas Affiliate) to B. Moorthy and by USPHS Grant CA32157 from the National Cancer Institute to Kurt Randerath.
- Abbreviations:
- MC
- 3-methylcholanthrene
- PAH
- polycyclic aromatic hydrocarbon
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- BP
- benzo[a]pyrene
- AHR
- Ah receptor
- AhRE
- Ah response elements
- ARNT
- Ah receptor nuclear translocator
- EROD
- ethoxyresorufinO-deethylase
- MROD
- methoxyresorufinO-demethylase
- AHH
- aryl hydrocarbon hydroxylase
- HRP
- horseradish peroxidase
- PAGE
- polyacrylamide gel electrophoresis
- CO
- corn oil
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- SSC
- sodium chloride sodium citrate
- DBA
- dibenz[ac]anthracene
- EMSA
- electrophoretic mobility shift assay
- Received December 13, 1999.
- Accepted March 9, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
