Temporal Variation and Identification of Factors Associated with Endogenous Retinoic Acid Isomers in Serum from Brazilian Women Erin M. Siegel, 1 Neal E. Craft, 2 Denise J. Roe, 1 Eliane Duarte-Franco, 4 Luisa L. Villa, 3 Eduardo L. Franco, 4,5 and Anna R. Giuliano 1 1 Cancer Prevention and Control Program, University of Arizona Cancer Center and Epidemiology and Biostatistics Division, Mel and Enid Zuckerman Arizona College of Public Health, Tucson, Arizona; 2 Craft Technologies, Inc., Wilson, North Carolina; 3 Ludwig Institute for Cancer Research, Sa ˜o Paulo, Brazil; and Departments of 4 Oncology and 5 Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada Abstract Objective: Retinoids (natural and synthetic derivatives of vitamin A) have cancer chemotherapeutic and chemopreventive activities. Retinoic acid (RA) treat- ment has been associated with significant regression of preneoplastic lesions. However, serious toxicity asso- ciated with some therapies has made long-term che- moprevention in healthy populations unfeasible. Recently, serum RA has been shown to increase in re- sponse to oral retinol (vitamin A) supplementation. Here, we assess the variability of circulating RA levels and the lifestyle, demographic, and nutritional factors that explain such variability. Method: Total RA concentration and the concentrations of RA isomers (all-trans -RA, 13-cis -RA, and 9-cis -RA) were measured by high-pressure liquid chromatogra- phy in serum samples obtained 4 months apart from 502 women participating in the Ludwig-McGill Cohort (Sa ˜o Paulo, Brazil). Results: The relative abundance of the three RA isomers was similar for each visit (baseline and month 4), with 13-cis -RA having the highest concentrations followed by 9-cis -RA and all-trans -RA. The within-person variability of total RA and individual isomers was low. Using multivariate logistic regression models (upper tertile versus low/middle tertile of serum RA), we found that age, race, oral contraceptive use, total number of pregnancies, and season of initial blood draw were significantly associated with at least one endogenous RA isomer level. All endogenous RA isomers were positively associated with serum retinol, B-carotene, and B-cryptoxanthin levels. Conclusion: These results have implications for the design of future epidemiologic studies focused on as- sessing RA-disease association and intervention stud- ies aimed at modulating RA levels. (Cancer Epidemiol Biomarkers Prev 2004;13(11):1693 – 703) Introduction Retinoic acid (RA) is required for many biological processes including vision, development, and reproduc- tion (1-3). RA mediates these activities by binding to nuclear retinoid receptors, members of the steroid hor- mone receptor superfamily (4), and altering transcrip- tional activity (1, 5). To date, two families of receptors have been identified, RA receptor (RAR) and retinoid X receptor (5). RAR binds all-trans -RA and 9-cis -RA with equal affinity, whereas retinoid X receptor preferentially binds 9-cis -RA (6). Each receptor family has at least three subtypes (a, h, and g), and within these subtypes, there are many different isoforms (7). Due to the different receptor isoforms, retinoid receptors can interact with a diverse number of receptors forming homodimers and heterodimers not only with retinoid receptors but also with other steroid hormone nuclear receptors such as vitamin D receptors and the estrogen receptor (8). Through this potent activity as transcriptional regu- lators, retinoids (natural and synthetic derivatives of vitamin A) have been shown to be cancer chemothera- peutic and chemopreventive (see also refs. 5, 9, 10 for reviews). RA treatment (all-trans -RA) has been associated with significant regression of several preneoplastic lesions, including oral leukoplakia (11), cervical dysplasia (12), and actinic keratoses (5). Although retinoid chemo- prevention is effective, there are toxicities associated with therapy such as varying degrees of teratogenicity and mucocutaneous cytotoxicity (5, 13). These toxicities make long-term chemoprevention among healthy populations with naturally occurring RA unfeasible. 13-Cis -RA (iso- tretinoin) and N-(4-hydroxyphenyl)retinamide (Fenreti- nide) have been shown to have lower toxicities, but it remains unclear if these drugs are able to induce retinoid receptor – mediated changes. An alternative retinoid che- moprevention approach is to develop a method for increasing endogenous concentrations of RA. Such an Received 3/5/04; revised 5/6/04; accepted 6/3/04. Grant support: National Cancer Institute grants CA70269 and CA81310, Canadian Institutes of Health Research grants MA-13647 and MOP-49396, Ludwig Institute for Cancer Research intramural grant, Canadian Institutes of Health Research Distinguished Scientist Award (E.L. Franco), and National Cancer Institute Cancer Prevention and Control predoctoral fellowship grant R25CA078447 (E.M. Siegel). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Presented in part at the AACR Annual Conference, San Francisco, California, 2002 and AACR Frontiers in Cancer Prevention Conference, Phoenix, Arizona, 2003. Requests for reprints: Anna R. Giuliano, H. Lee, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, MRC-2E, Tampa, FL 33612. Phone: 813-903-6820. E-mail: guiliano@moffitt.usf.edu Copyright D 2004 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 1693 Cancer Epidemiol Biomarkers Prev 2004;13(11). November 2004 Research. on October 19, 2021. © 2004 American Association for Cancer cebp.aacrjournals.org Downloaded from