Effect of chronic estrogen treatment of Syrian hamsters on microsomal enzymes mediating formation of catecholestrogens and their redox cycling: implications for carcinogenesis.
Estrogens have previously been shown to induce DNA damage in Syrian hamster kidney, a target organ of estrogen-induced cancer. The biochemical mechanism of DNA adduction has been postulated to involve free radicals generated by redox cycling of estrogens. As part of an examination of this postulate, we measured the effect of chronic estrogen treatment of hamsters on renal microsomal enzymes mediating catechol estrogen formation and free radical generation by redox cycling of catechol estrogens. In addition, the activities of the same enzymes were assayed in liver in which tumors do not develop under these conditions. At saturating substrate concentration, 2- and 4-hydroxyestradiol were formed in approximately equal amounts (26 and 28 pmol/mg protein/min, respectively), which is 1-2 orders of magnitude higher than reported previously. Estradiol treatment for 2 months decreased 2-hydroxylase activity per mg protein by 75% and 4-hydroxylase activity by 25%. Hepatic 2- and 4-hydroxylase activities were 1256 and 250 pmol/mg protein/min, respectively. Estrogen treatment decreased both activities by 40-60%. Basal peroxidatic activity of cytochrome P-450, the enzyme which oxidizes estrogen hydroquinones to quinones in the redox cycle, was 2.5-fold higher in liver than in kidney and did not change with estrogen treatment. However, when normalized for specific content of cytochrome P-450 the enzyme activity in kidney was 2.5-fold higher than in liver and increased further by 2-3-fold with chronic estrogen treatment. The activity of cytochrome P-450 reductase, which reduces quinones to hydroquinones in the estrogen redox cycle, was 6-fold higher in liver than in kidney of both control and estrogen-treated animals. When normalized for cytochrome P-450, the activity of this enzyme was similar in liver and kidney, but over 4-fold higher in kidney than liver after estrogen treatment. Basal concentrations of superoxide, a product of redox cycling, were 2-fold higher in liver than in kidney. Estrogen treatment did not affect this parameter in liver, but increased it in kidney by 40%. These data provide evidence for a preferential preservation of enzymes involved in estrogen activation.
Liehr
J G
JG
Department of Obstetrics and Gynecology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
Roy
D
D
Ari-Ulubelen
A
A
Bui
Q D
QD
Weisz
J
J
Strobel
H W
HW
D000818:Animals; D002273:Carcinogens; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003579:Cytochrome Reductases / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000096:biosynthesis; D004967:Estrogens / Q000494:pharmacology* / Q000633:toxicity; D002393:Estrogens, Catechol / Q000096:biosynthesis*; D005609:Free Radicals; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008647:Mesocricetus; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
D002273:Carcinogens; D004967:Estrogens; D002393:Estrogens, Catechol; D005609:Free Radicals; D013481:Superoxides; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; C001390:2-hydroxyestradiol; D003579:Cytochrome Reductases