TY - JOUR
T1 - Increased prevalence of dihydropyrimidine dehydrogenase deficiency in African-Americans compared with Caucasians
AU - Mattison, Lori Kay
AU - Fourie, Jeanne
AU - Desmond, Renee A.
AU - Modak, Anil
AU - Saif, Muhammad Wasif
AU - Diasio, Robert B.
PY - 2006/9/15
Y1 - 2006/9/15
N2 - 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.
AB - 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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U2 - 10.1158/1078-0432.CCR-06-0747
DO - 10.1158/1078-0432.CCR-06-0747
M3 - Article
C2 - 17000684
AN - SCOPUS:33749350447
SN - 1078-0432
VL - 12
SP - 5491
EP - 5495
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -