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Human dehydroepiandrosterone sulfotransferase pharmacogenetics: quantitative Western analysis and gene sequence
1Department of Pharmacology, Mayo Medical School/Mayo Clinic/Mayo Foundation, Rochester, MN 55905, USA.
The Journal of Steroid Biochemistry and Molecular Biology
|December 1, 1996
Summary
Genetic variations in the dehydroepiandrosterone sulfotransferase (DHEA ST) gene influence enzyme activity. A specific polymorphism in exon 4 significantly reduces DHEA ST expression and function, impacting steroid metabolism.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Dehydroepiandrosterone sulfotransferase (DHEA ST) is crucial for steroid metabolism.
- Human liver DHEA ST activity exhibits significant inter-individual variability, with a five-fold range and a bimodal distribution.
Purpose of the Study:
- To investigate the molecular basis for variations in human liver DHEA ST activity.
- To identify potential genetic polymorphisms in the DHEA ST gene (STD) associated with altered enzyme function.
Main Methods:
- Quantitative Western analysis of 92 human liver samples to correlate DHEA ST activity with protein levels.
- PCR amplification and sequencing of STD exons and 5'-flanking regions from liver DNA.
- Transient expression studies in COS-1 cells to assess the functional impact of identified polymorphisms.
Main Results:
- A significant correlation was observed between DHEA ST enzymatic activity and immunoreactive protein levels (r(s) = 0.635, P < 0.0001).
- Two genetic polymorphisms were identified: a T-->C transition in exon 2 (Met57Thr) and an A-->T transversion in exon 4 (Glu186Val).
- The exon 4 polymorphism (Glu186Val), when present, significantly decreased DHEA ST enzymatic activity and protein expression in transient expression studies.
Conclusions:
- Common genetic polymorphisms exist within the human STD gene.
- The Glu186Val polymorphism in DHEA ST exon 4 is associated with reduced enzyme activity and protein levels, potentially explaining some inter-individual variability in steroid metabolism.