Increased prevalence of dihydropyrimidine dehydrogenase deficiency in African-Americans compared with Caucasians.
OBJECTIVE
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.


METHODS
Healthy African-American (n=149) and Caucasian (n=109) volunteers were evaluated for DPD deficiency using both the [2-(13)C]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).


CONCLUSIONS
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.
Mattison
Lori Kay
LK
Division of Clinical Pharmacology and Toxicology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA.
Fourie
Jeanne
J
Desmond
Renee A
RA
Modak
Anil
A
Saif
Muhammad Wasif
MW
Diasio
Robert B
RB
D000328:Adult; D001741:Black or African American / Q000235:genetics* / Q000706:statistics & numerical data; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D001944:Breath Tests; D002245:Carbon Dioxide / Q000032:analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003430:Cross-Sectional Studies; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000097:blood / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D012727:Sex Characteristics; D044465:White People / Q000235:genetics* / Q000706:statistics & numerical data
D002245:Carbon Dioxide; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil