Abstract
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases and pyrimidine-based antimetabolites. Reduced DPD activity is associated with toxicity to 5-fluorouracil (5FU) therapy in cancer patients and with neurological abnormalities in paediatric patients. Although variant DPYD alleles have been identified in DPD-deficient patients, they do not adequately explain polymorphic DPD activity or associated clinical phenotypes in vivo. DPD may be transcriptionally regulated as mRNA levels correlate with activity and are differentially regulated in human tissues. A 1.85 kb 5' flanking region of the human DPYD gene was cloned and has transcriptional activity in cultured cells. Analysis of this 5' flanking: region in rhesus and cynomolgus monkeys demonstrated conservation (>96%) between humans and primates. Putative binding sites for ubiquitous and cell-specific factors were identified. A polymorphism that disrupts a putative gamma-interferon response element was identified in a cancer patient with reduced DPD activity and severe 5FU toxicity. Further insight into regulation of DPD expression may identify new avenues for the treatment of clinical problems associated with DPD deficiency. (C) 2000 academic Press.
| Original language | English |
|---|---|
| Pages (from-to) | 28-35 |
| Number of pages | 8 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 271 |
| Publication status | Published - 2000 |
Keywords
- dihydropyrimidine dehydrogenase
- promoter
- 5-fluorouracil
- toxicity
- transcription
- human
- rhesus
- cynomolgus
- polymorphism
- DIHYDROPYRIMIDINE DEHYDROGENASE-DEFICIENCY
- TRANSCRIPTION FACTORS
- 5-FLUOROURACIL TOXICITY
- MOLECULAR-BASIS
- LIVER
- FLUOROURACIL
- INTERFERON
- POPULATION
- INHIBITION
- PHENOTYPE
Cite this
Cloning and initial characterization of the human DPYD gene promoter. / Collie-Duguid, E S R ; Johnston, S J ; Powrie, R H ; Milano, G ; Etienne, M C ; Rochat, B ; Watson, G C ; McLeod, H L .
In: Biochemical and Biophysical Research Communications, Vol. 271, 2000, p. 28-35.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cloning and initial characterization of the human DPYD gene promoter
AU - Collie-Duguid, E S R
AU - Johnston, S J
AU - Powrie, R H
AU - Milano, G
AU - Etienne, M C
AU - Rochat, B
AU - Watson, G C
AU - McLeod, H L
PY - 2000
Y1 - 2000
N2 - Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases and pyrimidine-based antimetabolites. Reduced DPD activity is associated with toxicity to 5-fluorouracil (5FU) therapy in cancer patients and with neurological abnormalities in paediatric patients. Although variant DPYD alleles have been identified in DPD-deficient patients, they do not adequately explain polymorphic DPD activity or associated clinical phenotypes in vivo. DPD may be transcriptionally regulated as mRNA levels correlate with activity and are differentially regulated in human tissues. A 1.85 kb 5' flanking region of the human DPYD gene was cloned and has transcriptional activity in cultured cells. Analysis of this 5' flanking: region in rhesus and cynomolgus monkeys demonstrated conservation (>96%) between humans and primates. Putative binding sites for ubiquitous and cell-specific factors were identified. A polymorphism that disrupts a putative gamma-interferon response element was identified in a cancer patient with reduced DPD activity and severe 5FU toxicity. Further insight into regulation of DPD expression may identify new avenues for the treatment of clinical problems associated with DPD deficiency. (C) 2000 academic Press.
AB - Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases and pyrimidine-based antimetabolites. Reduced DPD activity is associated with toxicity to 5-fluorouracil (5FU) therapy in cancer patients and with neurological abnormalities in paediatric patients. Although variant DPYD alleles have been identified in DPD-deficient patients, they do not adequately explain polymorphic DPD activity or associated clinical phenotypes in vivo. DPD may be transcriptionally regulated as mRNA levels correlate with activity and are differentially regulated in human tissues. A 1.85 kb 5' flanking region of the human DPYD gene was cloned and has transcriptional activity in cultured cells. Analysis of this 5' flanking: region in rhesus and cynomolgus monkeys demonstrated conservation (>96%) between humans and primates. Putative binding sites for ubiquitous and cell-specific factors were identified. A polymorphism that disrupts a putative gamma-interferon response element was identified in a cancer patient with reduced DPD activity and severe 5FU toxicity. Further insight into regulation of DPD expression may identify new avenues for the treatment of clinical problems associated with DPD deficiency. (C) 2000 academic Press.
KW - dihydropyrimidine dehydrogenase
KW - promoter
KW - 5-fluorouracil
KW - toxicity
KW - transcription
KW - human
KW - rhesus
KW - cynomolgus
KW - polymorphism
KW - DIHYDROPYRIMIDINE DEHYDROGENASE-DEFICIENCY
KW - TRANSCRIPTION FACTORS
KW - 5-FLUOROURACIL TOXICITY
KW - MOLECULAR-BASIS
KW - LIVER
KW - FLUOROURACIL
KW - INTERFERON
KW - POPULATION
KW - INHIBITION
KW - PHENOTYPE
M3 - Article
VL - 271
SP - 28
EP - 35
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
ER -