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

Abstract

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 F 0.07 and 0.29 F 0.07 nmol/min/mg, respectively; P = 0.002). The prevalence of DPD deficiency was 3-fold higher in AfricanAmericans 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.5-Fluorouracil (5-FU) and its fluoropyrimidine derivatives (e.g., capecitabine) are widely prescribed in oncologic practice to treat gastrointestinal malignancies and are often used in the management of breast and head and neck cancer (1 -4). However, despite its widespread use, f31% of patients with advanced colorectal cancer who receive bolus 5-FU regimens experience grades 3 to 4 hematologic toxicities (5). The pharmacogenetic syndrome, dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2) deficiency, has been shown to predispose cancer patients to severe 5-FU toxicity (6 -9). In particular, it is estimated that 40% to 60% of patients with cancer who present with severe 5-FU toxicity are 11).Several studies show the pivotal role of DPD in 5-FU metabolism and response. Earlier biochemical studies showed that DPD, the initial and rate-limiting enzyme of the pyrimidine catabolic pathway, degrades uracil, thymine, and 5-FU to dihydrouracil, dihydrothymine, and 5-fluoro-dihydrouracil, respectively (12, 13). Pharmacokinetic evaluation has further shown that DPD catabolizes >80% of an administered dose of 5-FU, thereby determining the amount of 5-FU available for anabolism (7). Furthermore, data from combined pharmacokinetic/pharmacodyna...

Review: Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management

“…Clinical factors predictive for fluoropyrimidine-induced diarrhea are female sex, caucasian race and presence of diabetes [Zalcberg et al 1998;McCollum et al 2002;Meyerhardt et al 2004]. The gender-and race-related differences are possibly influenced by the variable activity of dihydropyrimidinedehydrogenase (DPD) [Mattison et al 2006a]. The leading polymorphism, which accounts for nearly 50% of nonfunctional alleles, is the DPYD*2A, resulting in a decreased drug clearance and prolonged exposure with severe toxicities.…”

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

“…Yet a recent summary of the data on DPYD*2A, including multiple studies of this variant alone or in combination with other common variants, showed a performance sensitivity (the percentage of actual patients with severe toxicity who were correctly identified by the allele) ranging between 6.3 and 83%, with a median sensitivity of 30% (Yen and McLeod, 2007). Even more importantly, despite the fact that the prevalence of functional enzymatic DPD deficiency is higher in African Americans (Mattison et al, 2006), the DPYD*2A variant is not even present in African Americans (van Kuilenburg, 2004), making such testing of limited generalizability and utility. Direct to consumer genetic testing services like 23andMe fail to convey these nuances: 23andMe Inc (2011) advertises genetic testing for 5-FU sensitivity, but their testing consists only of genotyping of the DPYD*2A variant, and it is not mentioned directly on their website that there is likely to be no relevant information about 5-FU susceptibility for certain ethnic groups like African Americans.…”

Evaluation of Correlation Between Serum Level of Dihydropyrimidine Dehydrogenase Enzyme and Capecitabine Induced Adverse Reaction

“…So far 39 different mutations are recognized in the DPD gene (5). This syndrome classically causes early onset and exaggerated toxicity, which clinically presents with mucositis, diarrhea, myelosuppression, HFS, neutropenia, and rarely, but characteristically, neurologic deficits (6). This syndrome is evaluated in different population in several studies.…”