Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota, USA.
Clin Pharmacol Ther. 2013 Jul;94(1):158-66. doi: 10.1038/clpt.2013.69. Epub 2013 Apr 3.
5-Fluorouracil (5-FU) is used to treat many aggressive cancers, such as those of the colon, breast, and head and neck. The responses to 5-FU, with respect to both toxicity and efficacy, vary among racial groups, potentially because of variability in the activity levels of the enzyme dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene). In this study, the genetic associations between DPYD variations and circulating mononuclear-cell DPD enzyme activity were evaluated in 94 African-American and 81 European-American volunteers. The DPYD-Y186C variant was unique to individuals of African ancestry, and DPD activity was 46% lower in carriers as compared with noncarriers (279 ± 35 vs. 514 ± 168 pmol 5-FU min(-1) mg(-1); P = 0.00029). In this study, 26% of the African Americans with reduced DPD activity were carriers of Y186C. In the African-American cohort, after excluding Y186C carriers, homozygous carriers of C29R showed 27% higher DPD activity as compared with noncarriers (609 ± 152 and 480 ± 152 pmol 5-FU min(-1) mg(-1), respectively; P = 0.013).
5-氟尿嘧啶（5-FU）用于治疗多种侵袭性癌症，如结肠癌、乳腺癌和头颈部癌症。5-FU 的反应（包括毒性和疗效）在不同种族群体之间存在差异，这可能是由于二氢嘧啶脱氢酶（DPD，由 DPYD 基因编码）的酶活性水平存在差异。在这项研究中，评估了 94 名非裔美国人和 81 名欧洲裔美国志愿者中 DPYD 变异与循环单核细胞 DPD 酶活性之间的遗传关联。DPYD-Y186C 变异仅存在于非洲血统个体中，与非携带者相比，携带者的 DPD 活性降低了 46%（279±35 与 514±168 pmol 5-FU min(-1) mg(-1)；P=0.00029）。在这项研究中，26%的 DPD 活性降低的非裔美国人是 Y186C 的携带者。在非裔美国人队列中，排除 Y186C 携带者后，C29R 纯合子携带者的 DPD 活性比非携带者高 27%（分别为 609±152 和 480±152 pmol 5-FU min(-1) mg(-1)；P=0.013）。
