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Structural Organization of the Human Dihydropyrimidine Dehydrogenase Gene¹

Department of Pharmacology and Toxicology, University of Alabama, Birmingham, Alabama 35294

Deficiency of the pyrimidine catabolic enzyme, dihydropyrimidine dehydrogenase (DPD), has been shown to be responsible for a pharmacogenetic syndrome in which administration of 5-fluorouracil is associated with severe and potentially life-threatening toxicity. Following the recent availability of the cDNA for DPD, there were initial reports of several molecular defects (point mutations, deletions due to exon skipping) that were suggested as a potential molecular basis for DPD deficiency, even before the complete physical structure of the DPD gene was known. To understand the mechanism responsible for DPD deficiency, we have determined the genomic structure and organization of the human DPD gene. The gene is approximately 150 kb in length, and it consists of 23 exons, ranging in size from 69 to 1404 bp. The sequences of intronic regions flanking the exon boundaries have been determined. The physical map of the DPD gene should permit development of rapid assays to detect point mutations or small deletions in the DPD gene associated with 5-fluorouracil toxicity.

¹ This work was supported by United States Public Health Service Grant CA 62164. N. A. is a recipient of a grant from the National Cancer Institute/European Organization for Research and Treatment of Cancer Exchange Program and the IARC. S. T. was supported by the German-American Fulbright Commission (Commission for Educational Exchange between the United States and Germany).

² Present address: Medizinische Hochschule Hannover, Zentrum Biochemie, Abteilung I Physiologische Chemie, Karl-Wiechert-Allee 9, D-30625 Hannover, Germany.

³ To whom requests for reprints should be addressed, at Department of Pharmacology and Toxicology, Room 101, Volker Hall, University of Alabama, Birmingham, AL 35294. Phone: (205) 934-4578; Fax: (205) 934-8240.

Received 1/10/97. Accepted 3/26/97.

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