AROMATASE INHIBITORS (CYP19) : STRUCTURAL MODIFICATIONS AND IMPORTANCE IN THERAPY

Cilj ovog diplomskog rada je proučavanje mogućeg nastanka karcinoma dojke, uzrokovanog metaboličkim promjenama na estrogenim hormonima, a pod utjecajem enzimskih sustava koji u tim reakcijama sudjeluju. Prikazani su glavni metabolički putovi estrogenih hormona kao i metaboličke promjene lijekova koji se koriste u liječenju karcinoma dojke s posebnim naglaskom na inhibitore aromataze. Opisane su reakcije I. i II. faze biotransformacije kroz koje prolazi najpotentnija treća generacija inhibitora aromataze – anastrozol, letrozol i eksemestan. Anastrozol podliježe N-dealkilaciji, hidroksilaciji i glukuronidaciji. Letrozol podliježe N-dealkilaciji, te pod utjecajem enzima CYP ostaje produkt koji se zove karbinol koji potom podliježe procesu glukuronidacije. Eksemestan podliježe redukciji keto skupine u položaju 17, oksidaciji metilenske grupe u položaju 6, te glukuronidaciji. Opisane su i najvažnije interakcije anastrozola, letrozola i eksemestana.The aim of this graduate thesis is to study the possible emergence of breast cancer caused by metabolic changes on estrogen hormones and under the influence of the enzymatic systems involved in these reactions. The main metabolic pathways of estrogenic hormones have been described as well as the metabolic changes of the drugs used in the treatment of breast cancer with particular emphasis on aromatase inhibitors. The reactions of biotransformation of phases I and II of the most potent third generation of aromatase inhibitors - anastrozole, letrozole and exemestane have been described. Anastrozole is subjected to N-dealkylation, hydroxylation and glucuronidation. Letrozole is subjected to N-dealkylation, and under the influence of the CYP enzymes remains a product called carbinol which is then subjected to the glucuronidation process. The exemestane is subjected to reduction of the keto group at position 17, oxidation of the methylene group at position 6, and glucuronidation. The most important interactions of anastrozole, letrozole and exemestane are also described