عنوان

Potential carcinogenic mechanisms for premarin estrogens

Number

TLpq304482277

.Language of Text, Soundtrack etc

انگلیسی

Title Proper

Potential carcinogenic mechanisms for premarin estrogens

General Material Designation

[Thesis]

First Statement of Responsibility

L. Shen

Subsequent Statement of Responsibility

J. L. Bolton

Name of Publisher, Distributor, etc.

University of Illinois at Chicago, Health Sciences Center

Date of Publication, Distribution, etc.

1998

Specific Material Designation and Extent of Item

179

Dissertation or thesis details and type of degree

Ph.D.

Body granting the degree

University of Illinois at Chicago, Health Sciences Center

Text preceding or following the note

1998

Text of Note

There is a clear association between excessive exposure to estrogens and the development of cancer in several tissues including breast and endometrium. Premarin is the most widely dispensed prescription for estrogen replacement therapy in the U.S.A. in 1995. It contains 46% endogenous estrogens and 54% unsaturated estrogens including equilin and equilenin. The endogenous estrogens, 17usd\betausd-estradiol and estrone are each metabolized to two catechol metabolites; i.e. for estrone, 2-hydroxyestrone (2-OHE) and 4-hydroxyestrone (4-OHE). These catechols are easily oxidized to o-quinones. The half lives of 2-OHE- and 4-OHE-o-quinones were determined under physiological conditions, to be 42 sec and 12 min respectively. In the absence of GSH, both o-quinone isomerized to quinone methides at the same rate as the disappearance of the o-quinone. 4-OHE rather than 2-OHE, is a renal carcinogen in male syrian golden hamster. This may be because the 4-OHE-o-quinone is 17-fold more stable than 2-OHE-o-quinone. Equilenin or its 17-hydroxylated analogs make up to 15% of Premarin, and yet there is very little information on the human metabolism of these estrogens. We have synthesized the catechol metabolite of equilenin, 4-hydroxyequilenin (4-OHEN) and found aromatization of the B-ring dramatically affected the formation of the o-quinone, the isomerization of the o-quinone to quinone methides, and the reactivity of the quinoids. Interestingly, 4-OHEN autoxidized to a stable o-quinone (t{1/2} = 2.3 hours) under physiological conditions, which readily entered into a redox couple with the semiquinone radical catalyzed by NAD(P)H, P450 reductase, DT-diaphorase, or cytosol from human melanoma cells. Significant NAD(P)H and oxygen consumption were detected during the redox cycling of 4-OHEN. In addition, the generation of reactive oxygen species caused DNA single strand breaks in a dose and time dependent manner. These data suggested that reduction of estrogen-o-quinones could represent a cytotoxic mechanism involving consumption of NAD(P)H as well as formation of reactive oxygen species leading to oxidative stress which could cause DNA damage. In addition to oxidative damage, 4-OHEN-semiquinone radical reacted with 2-deoxynucleosides generating very unusual cyclic adducts. 2-Deoxyguanosine (dG), 2-deoxyadenosine (dA) or 2-deoxycytosine (dC), all gave four diastereoisomers but no product was observed for thymidine. The structures of these adducts were determined by mass spectrometry and NMR. In the reaction of 4-OHEN with DNA, significant apurinic sites were produced before DNA hydrolysis. When the DNA was hydrolyzed to deoxynucleosides, only one isomer of 4-OHEN-dG and 4-OHEN-dC were observed suggesting that there was regiospecificity in the reaction of DNA with the 4-OHEN-semiquinone radical. These data suggested that several different types of DNA lesions could be expected from 4-OHEN including apurinic sites, bulky stable adducts, and oxidized damage to DNA. The production of semiquinone radical derived DNA adducts and reactive oxygen species could play a role in the carcinogenic effects of Premarin estrogens.

DNA damage

Health and environmental sciences

Oncology

Pharmaceuticals

Pharmacology

Pure sciences

J. L. Bolton

L. Shen

Electronic name

p

[Thesis]

276903

a

Y