DNA adduct formation in liver and kidney of male Syrian hamsters treated with estrogen and/or alpha-naphthoflavone.
Chronic administration of estrogens to male Syrian hamsters induces kidney tumors. Co-administration of estrogen plus alpha-naphthoflavone (ANF) suppresses this kidney carcinogenesis but induces liver tumors instead. In an attempt to elucidate the mechanism of the switch from estrogen-induced kidney to liver carcinogenesis in response to ANF treatment, patterns of kidney and liver DNA adducts were investigated by 32P-postlabeling analysis and compared to controls. Chronic treatment of hamsters with ANF alone or in combination with estradiol resulted in a flavone-specific DNA adduct pattern in livers of these animals. These spots, adducts 1 and 2, on 32P-postlabeling maps were taken as evidence of covalent ANF-DNA modifications. The kidney-specific estrogen-induced indirect DNA adducts, observed previously in hamsters treated chronically with estrogen, occurred in renal but not hepatic DNA of animals treated with estradiol alone or in combination with ANF. Pretreatment of hamsters with ANF for 3 days decreased by 75-80% the hepatic and renal diethylstilbestrol (DES)-DNA adducts, which are formed after injection of a single large dose of DES. It is concluded from these changes in DNA adduct patterns and levels that estrogen quinone-DNA adduction may play an etiological role in estrogen-induced kidney cancer. The prevention of estrogen-induced kidney tumors by ANF co-treatment may be a consequence of the decrease in renal concentrations of these adducts in response to ANF. Hepatic concentrations of estrogen quinone-DNA adducts also decrease, but ANF-DNA adducts, observed only in liver, may assume an etiological role in the induction of hepatomas.
Liehr
J G
JG
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77550.
Gladek
A
A
Macatee
T
T
Randerath
E
E
Randerath
K
K
D000818:Animals; D001571:Benzoflavones / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts; D004054:Diethylstilbestrol / Q000378:metabolism / Q000633:toxicity; D004347:Drug Interactions; D004357:Drug Synergism; D004967:Estrogens / Q000378:metabolism / Q000633:toxicity*; D007668:Kidney / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000139:chemically induced; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D008647:Mesocricetus
D001571:Benzoflavones; D018736:DNA Adducts; D004967:Estrogens; C068150:alpha-naphthoflavone-DNA adduct; C068149:diethylstilbesterol-DNA adduct; C011512:alpha-naphthoflavone; D004054:Diethylstilbestrol; D004247:DNA