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Increased Prevalence of Dihydropyrimidine Dehydrogenase Deficiency in African-Americans Compared with Caucasians

Authors' Affiliations: Divisions of ¹ Clinical Pharmacology and Toxicology, and ² Biostatistics, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama; ³ Cambridge Isotope Laboratories, Inc., Andover, Massachusetts; and ⁴ Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Robert B. Diasio, Division of Clinical Pharmacology, Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1824 6th Avenue South, Wallace Tumor Institute, Room 620, Birmingham, AL 35294-3300. Phone: 205-934-4578; Fax: 205-975-5650; E-mail: robert.diasio{at}ccc.uab.edu.

Purpose: African-American patients with colorectal cancer were observed to have increased 5-fluorouracil (5-FU)–associated toxicity (leukopenia and anemia) and decreased overall survival compared with Caucasian patients. One potential source for this disparity may be differences in 5-FU metabolism. Dihydropyrimidine dehydrogenase (DPD), the initial and rate-limiting enzyme of 5-FU catabolism, has previously been shown to have significant interpatient variability in activity. Several studies have linked reduced DPD activity to the development of 5-FU toxicity. Although the distribution of DPD enzyme activity and the frequency of DPD deficiency have been well characterized in the Caucasian population, the distribution of DPD enzyme activity and the frequency of DPD deficiency in the African-American population are unknown.

Experimental Design: Healthy African-American (n = 149) and Caucasian (n = 109) volunteers were evaluated for DPD deficiency using both the [2-¹³C]uracil breath test and peripheral blood mononuclear cell DPD radioassay.

Results: African-Americans showed significantly reduced peripheral blood mononuclear cell DPD enzyme activity compared with Caucasians (0.26 ± 0.07 and 0.29 ± 0.07 nmol/min/mg, respectively; P = 0.002). The prevalence of DPD deficiency was 3-fold higher in African-Americans compared with Caucasians (8.0% and 2.8%, respectively; P = 0.07). African-American women showed the highest prevalence of DPD deficiency compared with African-American men, Caucasian women, and Caucasian men (12.3%, 4.0%, 3.5%, and 1.9%, respectively).

Conclusion: These results indicate that African-Americans, particularly African-American women, have significantly reduced DPD enzyme activity compared with Caucasians, which may predispose this population to more 5-FU toxicity.

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