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Dissertation
The effect of phenytoin on transcription of key proteins of fatty acid metabolism in hyperkalemic periodic paralysis
Doctor of Philosophy (Ph.D.), Allegheny University of the Health Sciences
May 1997
DOI:
https://doi.org/10.17918/00009702
Abstract
Hyperkalemic penodic paralysis (HPP) is an autosomal dominant skeletal muscle disease characterized by any one of several sodium channel gene point mutations in the adult form of the [alpha] subunit (SkM1). The sodium channel defect is associated with a delayed inactivation of fast inward sodium current. It has been observed that co-expression of the Beta 1 ([beta]1) subunit with SkM1 is necessary for the normal kinetics of sodium channel inactivation and may be necessary for proper placement and function of SkM1 in the membrane. There is evidence that the primary defect in the sodium channel may cause a secondary alteration in triglyceride-associated fatty acid metabolism (TAFAM). The hypothesis to be tested was that TAFAM may influence the [beta]1/SkM1 interaction, contribute to the paralysis, and be involved in the action of the clinically efficacious drug phenytoin. It was the aim of this study to examine the effect of phenytoin treatment on the transcriptional regulation of the [beta]1 subunit and three key proteins in TAFAM: hormone sensitive lipase (HSL), carnitine palmitoyltransferase (CPT), and fatty acid binding protein (FABP). These transcripts were quantitated by competitive reverse transcription PCR in primary cultures of equine nondifferentiated and differentiated skeletal muscle from control (n = 3), heterozygote HPP (n = 3), and homozygote-affected HPP (n = 3) horses. Homozygote-affected cultures expressed significantly more [beta]1 transcript in differentiated cultures than either heterozygote or control cultures. Phenytoin decreased [beta]1 transcript in eight out of nine nondifferentiated cultures when genotypes were pooled and increased [beta]1 transcript in eight out of nine differentiated cultures. Homozygote-affected cultures expressed significantly less HSL transcript in both nondifferentiated and differentiated cultures than either heterozygote or control cultures. Phenytoin had no effect on HSL expression in nondifferentiated cultures and selectively increased HSL transcript in homozygote-affected differentiated cultures, abolishing the difference between genotypes. The level of CPT and FABP transcription was stable across genotype, differentiation, and phenytoin treatment. We conclude that these results suggest that the primary defect in HPP may secondarily increase [beta]1 and decrease HSL transcript levels and that the therapeutic action of phenytoin may involve regulation of [beta]1 and HSL transcription.
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Details
- Title
- The effect of phenytoin on transcription of key proteins of fatty acid metabolism in hyperkalemic periodic paralysis
- Creators
- Michelle Lynne Yudkowsky
- Awarding Institution
- Allegheny University of the Health Sciences
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Allegheny University of the Health Sciences; Philadelphia, Pennsylvania
- Number of pages
- ix, 155 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Allegheny University of the Health Sciences (1996-1998)
- Other Identifier
- 991021888844504721