Localization of estrogen-induced DNA adducts and cytochrome P-450 activity at the site of renal carcinogenesis in the hamster kidney.
Renal carcinoma in male Syrian hamsters, induced by chronic administration of estradiol for 5-7 months, is known to arise in the cortex at the cortico-medullary junction. In this in vivo model for hormonal carcinogenesis, estrogen-induced covalent DNA adducts have previously been observed in whole kidney and have been postulated to be involved in tumor induction. In the present study, the intrarenal distribution of estrogen-induced DNA modification and estrogen metabolizing enzymes were investigated in male Syrian hamsters to ascertain a role of metabolism and adduct formation in estrogen-induced carcinogenesis. The highest estrogen-induced DNA adduct concentrations as measured by 32P-postlabeling analysis were found in the renal cortex of hamsters treated with estradiol for 7 months. Total adduct levels in medullary DNA were approximately one-half of those found in cortex. Cytochrome P-450 enzymes were detected only in microsomes of kidney cortex (approximately 0.8 +/- 0.6 nmol P-450/mg protein) but not medulla of untreated male Syrian hamsters. Prostaglandin endoperoxide synthase activity in kidney cortical microsomes was 1/5 of the activity found in medullary microsomes. Thus, microsomal cytochrome P-450 levels and estrogen-induced DNA adduct formation were highest in hamster kidney cortex, the origin of renal tumorigenesis. It is postulated that estrogen metabolism by cytochrome P-450 enzymes leading to covalent DNA modification plays a role in hormonal carcinogenesis in the hamster kidney.
D000818:Animals; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004967:Estrogens / Q000378:metabolism / Q000633:toxicity*; D007668:Kidney / Q000032:analysis*; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D008861:Microsomes / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis
D004967:Estrogens; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D011451:Prostaglandin-Endoperoxide Synthases