Reactions of Xanthine Oxidase and Aromatase Inhibitor - Research Paper Example

Reactions of xanthine oxidase and aromatase inhibitor Aromatase inhibitor represent a class of antiestrogens, a drug that inhibits the enzyme aromatase by lowering the level of estrogen estradiol ,by process called aromatization. There are two types: first one is irreversible steroidal inhibitor and the second one is non-steroidal inhibitor such as anatrazole which inhibits the enzymes by reversible competition. In many tissues, such as: adrenal glands, ovaries, placenta, testicles, adipose tissue and brain it catalyzes the conversion of testosterone to estradiol. Aromatase inhibitor has no influence on estrogen output from ovaries, but it has influence by interfering with the body’s use of aromatase. Breast cancer, as well as ovarian cancer, is a large problem of medicine and both are life treating, especially for women. These cancers are of particular importance because they are promoted by estrogen. In 2000, approximately 130,000 women died of breast cancer; nearly two thirds of these women were postmenopausal. In pre-menopausal women estrogen is produced in the ovaries, so reducing estrogen from other sources it not important, but in post menopausal women most of the estrogen in the body is produced in the adrenal gland from conversion of androgens and also from adipose tissue through special enzyme called aromatase. The large influence of the estrogen produced outside the ovaries by aromatization is clear. In postmenopausal women, their estrogen comes from the actions of atomatase-final step in the pathway of estrogen biosynthesis by creating an aromating ring in the steroid molecule, and so its inhibitor may be used to treat estrogen tumors, and so, effective treatment in breast cancer is aromatase inhibitor. Also, it is used in women when their ovaries are no longer producing estrogen. It is not the same in premenopausal women or the opposite effects appear, the main estrogen comes up from ovaries, not by conversion androgen to estrogen, so blocking aromatization effects does not increase the androgen production. According to clinical researches, a correlation has been establishes between estrogen receptors and the growth of breast cancer and so effective therapy can be made by aromatase inhibitor working more efficient then tamoxifen. The hormone estrogen delivers growth thru signals to the hormone receptors, so less estrogen in the body leads to fewer growth signals and stopping the growth of cancer. Now medical experts consider aromatase inhibitor for postmenopausal women with invasive hormone receptor positive for breast cancer, in early and advanced stage. Aromatase inhibitor, according to research, can stimulate ovulation– can treat infertility. According to 65 patients included in the studies, drugs can suppress estrogen production in endometriosis, and reduces pain and chance of endometriosis in combination with hormonal treatment. It is significant to mention that there should be no long-term use because it may cause bone loss. It also helps bodybuilders, who take anabolic steroids from being converted to estrogen such as in the case of gynecomastia. In one recent study, however, aromatase inhibitors were found to be no more successful at treating pubertal gynecomastia than a placebo. Aromatase inhibitors have also been shown to reverse age-related declines in testosterone, as well as primary hypogonadism. The third generation drugs: anastrozole, letrozole and exemestane has given remarkable specificity and potency. Leading thru initial results from clinical trials, these agents will become the cornerstones of future endocrine therapy as a successful rational drug. It is important that the aromatase inhibitor have additional benefits thru pleiotropic effects as a particular role in preventing cancer or treating benign conditions. Xantine oxidase, a form of enzyme xantine oxidoreductase, is molybdoprotein containing flavoprotein and consists of two subunits of approximately 145 KDa. Generally, it occurs in vivo as an NAD depended cytosolic dehidrogenase enzyme. It can oxidize NADH with the concomitant formation of reactive oxygen species. It is a part of different biochemical reactions including the hydroxylation of various purines, pterines and aromatic heterocycles, as well as aliphatic and aromatic aldehydes, thereby contributing to the detoxification or activation of endogenous compounds and xenobiotics. It is widely distributed in mammalian tissue, liver, lungs, kidneys, heart, brain and plasma, and its main propose is making uric acid thru purines hypoxanthine and xanhtine. In the reaction with xanhtine to form uric acid an oxygen atom is transferred from molybdenum to xanthine. The transformation can appear thru addition of water because wherever molybdenum contains oxidoreductase, the oxygen atom introduced by XO originates from water rather than molybdenum. Its responsible for a medical condition known as gout and also for hiperuricemia, caused by deposition of uric acid which lead to painful inflammation. It has an important role as a biological source in the production of oxygen –derivate free radicals which contribute to oxidative damage of the liver tissue connected to the formation of serious inflammation, cancer , arteriosclerosis and aging, and certain lipid, protein and nucleic acids damage. It has important role in pathogenesis of shock, acute respiratory distress syndrome , inflammatory bowel disease and heart failure, which established the essences of XO inhibitor. Hidekazu Suzuki made a study in which he came to the conclusion that increasing the activity of XO ,an oxygen producing enzyme , plays important role in increasing arteriolar tone in spontaneous hypertensive rats. Enzyme reaction transfer electrons from hypoxanthine to ureic acid are coupled with reduction of molecular oxygen into superoxide anions. XO has been considered to play a critical role in pathogenesis of microvascular changes. Elevation from XO activities come from overproduction of oxyradicals in and around microvessels, which cause pathological response through a variety of mechanisms. According to Sukirti Karla, the reduction of drug available for therapy is anticancer drug 6.mercaptopurine(6MP) which is made by metabolic clearance thru xanthine oxidase, producing 6-thiouric acid excreted in urine. The need of preferential XOD inhibitor that inhibits 6MP transformation and leaves xantine metabolism unaffected is succeed by 2 unique inhibitors 2-amino-6-hydroxy-8-mercaptopurine (AHMP) and 2-amino-6-purinethiol (APT) whose administration of either of them with major atileukemic drug 6MP might serve as a good combination of cancer chemotherapy . In vitro studies in isolated hearts have demonstrates that the progressive development of heart failure is associated with myocardial XO levels, which contributes to an encashment of oxidative stress. During the researches has been found correlation between level of uric acid and the severity of chronic inflammation- measured by plasma receptors and so, the patient has increased circulation urine acid level and increased myocardial XO activity. Inherited deficiency leads to xantiuria and a multiple organ failure syndrome characterized by the deposition of xanthine in various tissues. Also there is xanthine oxydase deficiency II caused by deficiency of the enzyme xanthine dehygdrogenase and aldexide oxydase, enzymes needed to metabolize xanthine , characterized by excessive levels of xantine in urine. The main symptoms are kidney failure by kidney stone in severe cases. References: 1. Harrison, Roger. “Structure and function of xanthine oxidoreductase: where are we now?” Free Radical Biology and Medicine 15 September 2002, Vol 33: 774-779 2. Kalra, Sukirti. “Preferential inhibition of xanthine oxidase by 2-amino-6-hydroxy-8-mercaptopurine and 2-amino-6-purine thiol.” BMC Biochemistry 18 May 2007:1-11 3. Parnham, Michael J. and Jacques Bruinvels. Aromatase inhibitors. Berlin: Birkhäuser Basel, 2008. 4. Suzuki, Hidekazu. “Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats.” National Academy of Sciences April 1998, Vol 95: 4754-4759 Read More