In the US 32,000 case of endometrial cancer and 13,000 cases of cervical cancer were diagnosed in 1992 (>600,000 worldwide). These two sites in the uterus are less than 10 cm apart. Cigarette smoking substantially increases the risk of cervical cancer (approximately 3-fold), but significantly decreases the incidence of endometrial cancer (relative risk=0.4). Our principal goal is to examine one of the probable mechanisms for this differential effect of cigarette smoke on uterine neoplasia. (I) Our first hypothesis is that in patients with squamous cell cervical cancer, the levels of one or more of the cytochrome P450 isozymes (P4501A1 and P4503A4/5) are increased. These enzymes activate procarcinogens, from cigarette smoke, to reactive metabolites (e.g. benzo(a)pyrene (BP) to BP-diolepoxide (BPDE)) which form DNA adducts, ultimately leading to mutations and neoplasia. (II) The second hypothesis is that some individuals may be more vulnerable to cervical or endometrial cancer due to deficiencies of the detoxifying enzymes, gluthothione S-transferase (GST) and epoxide hydrolase (EH). (III) Our final hypothesis is that induction of the P450 enzymes plays a key role in the decreased risk of endometrial cancer in smokers. We postulate that the increase in levels of P4501A1, in addition to endometrial levels of P4503A7 (linked to estrogen biosynthesis) plays a key role in determining """"""""estrogenic exposure"""""""" of the endometrium. The enzymes to be investigated are also important in the activation/detoxification of other carcinogens. Therefore our studies may help determine the role of not only BP but other carcinogens in uterine neoplasia.
Our specific aims are 1) To measure P4501A1, 3A3/4, 3A7, EH and GST activity in the endometrium, endocervix and squamous cells of the cervix of smokers and nonsmokers with and without neoplasia. 2) To immunohistochemically examine the distribution of these enzymes in the regions cited in aim #1. 3) To incubate [H3]BP with various uterine tissues in vitro and measure [3H]BPDE-DNA adducts and BP metabolites by HPLC. 4) To assess the expression of P4501A1 by probing uterine tissue with polymerase chain reaction using isoform specific oligonucleotides. We have found significant P4501A1 activity (n=62) but no P4501A2 activity (n=12) in endometrial (approximately 2-fold) tissues. GST activity in patients with endometrial neoplasia was lower than in patients without neoplasia, whereas P4501A1 activity was higher. P4503A3/4 activity was below detectable limits in endometrial tissues. Our ultimate goal is to identify high risk populations by measuring the genetic expression of relevant enzymes in cervical scrapings or peripheral blood cells.
| Sarkar, Mohamadi A; Vadlamuri, Vijay; Ghosh, Shobha et al. (2003) Expression and cyclic variability of CYP3A4 and CYP3A7 isoforms in human endometrium and cervix during the menstrual cycle. Drug Metab Dispos 31:1-6 |
| Rege, Bhaskar; March, Clark; Sarkar, Mohamadi A (2002) Development of a rapid and sensitive high-performance liquid chromatographic method to determine CYP2D6 phenotype in human liver microsomes. Biomed Chromatogr 16:31-40 |
| Vadlamuri, S V; Glover, D D; Turner, T et al. (1998) Regiospecific expression of cytochrome P4501A1 and 1B1 in human uterine tissue. Cancer Lett 122:143-50 |
