The metabolism of 17β-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer

Abstract

Electron spin resonance (ESR) spectroscopy and oxygen consumption measurements using a Clark-type oxygen electrode have been used to study the metabolism of the estrogen 17 beta-estradiol by lactoperoxidase. Evidence for a one-electron oxidation of estradiol to its reactive phenoxyl radical intermediate is presented. The phenoxyl radical metabolite abstracts hydrogen from reduced glutathione generating the glutathione thiyl radical, which is spin trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and subsequently detected by ESR spectroscopy. In the absence of DMPO, molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. Similarly, the estradiol phenoxyl radical abstracts hydrogen from reduced beta-nicotinamide-adenine dinucleotide (NADH) to generate the NAD. radical. The NAD. radical is not spin trapped by DMPO, but instead reduces molecular oxygen to the superoxide radical, which is then spin-trapped by DMPO. The superoxide generated may either spontaneously dismutate to form hydrogen peroxide or react with another NADH to form NAD., thus propagating a chain reaction leading to oxygen consumption and hydrogen peroxide accumulation. Ascorbate inhibits oxygen consumption when estradiol is metabolized in the presence of either glutathione or NADH by reducing radical intermediates back to their parent molecules and forming the relatively stable ascorbate radical. These results demonstrate that the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence. The accumulation of intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently reported for female breast cancer tissue.

The Effects of Ascorbic Acid on the Estrogen/Progesteron Levels in the Isolated Rabbit Uterine Muscle

“…Ascorbate inhibits oxygen consumption when estradiol is metabolized in the presence of either glutathione or nicotinamide adenine dinucleotide (NADH) by reducing radical intermediates back to their parent molecules and forming the relatively stable ascorbate radical. The accumulation of intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently reported for female breast cancer tissue [4].…”

Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases

“…In majority of breast carcinomas the oxidative stress can be induced by the over expression of thymidine phosphorylase enzyme which catabolizes thymidine to thymine and 2-deoxy-D-ribose-1-phosphate; the latter is a powerful reducing sugar that rapidly glycates proteins, generating oxygen radicals within the carcinoma cell [137]. Another breast specific mechanism of oxidative stress induction involves a mammary gland specific lactoperoxidase enzyme catalyzed one electron oxidation of 17-b-oestradiol to a reactive phenoxyl radical [138].…”

Roles of Oxidative Stress in the Development and Progression of Breast Cancer

“…A rise in gene expression of thymidine phosphorylase in breast tumor cells is the main cause of oxidative stress in these patients (Brown and Bicknell, 2001). Lactoperoxidase enzyme involved in the metabolism of estrogenic hormone is produced in the mammary gland via the oxidation of 17-estradiol panoxyl radicals, which causes oxidative stress in breast carcinoma (Sipe et al, 1994). Inflammation, a process in a variety of cancers, also takes place in breast cancer and involves immune cells, including macrophages and neutrophils, in the immune response.…”