Inhibition of Riboflavin Metabolism in Cardiac and Skeletal Muscles of Rats by Quinacrine and Tetracycline

Dutta, Purabi; Raiczyk, Glenn B.; Pinto, John T.

doi:10.3164/jcbn.4.203

Cited by 3 publications

(2 citation statements)

References 14 publications

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“…This knowledge gap has possible implications for disease prevention, because a variety of factors can cause riboflavin depletion, including alcohol consumption (19,20), genetic defects of riboflavin transporter genes (19,20), impaired conversion of riboflavin to its coenzyme forms in persons with thyroid hormone insufficiency (21), and abnormal riboflavin metabolism such as inhibition of the incorporation of riboflavin into FAD in response to treatment with tricyclic and tetracyclic compounds such as chlorpromazine, tetracycline, and adriamycin (22,23). Note that current recommendations for riboflavin intake are largely based on studies using the FAD-dependent glutathione reductase as a marker of riboflavin nutrition, without considering the potentially more subtle FAD-dependent changes in the epigenome (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Regulation of the Albumin Gene Depends on the Removal of Histone Methylation Marks by the FAD-Dependent Monoamine Oxidase Lysine-Specific Demethylase 1 in HepG2 Human Hepatocarcinoma Cells

Liu

Zempleni

2014

The Journal of Nutrition

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Lysine-specific demethylase (LSD) 1 is an FAD-dependent demethylase that catalyzes the removal of methyl groups from lysine-4 in histone H3, thereby mediating gene repression. Here we tested the hypothesis that riboflavin deficiency causes a loss of LSD1 activity in HepG2 human hepatocarcinoma cells, leading to an accumulation of lysine-4-dimethylated histone H3 (H3K4me2) marks in the albumin promoter and aberrant upregulation of albumin expression. Cells were cultured in riboflavin-defined media providing riboflavin at concentrations representing moderately deficient (3.1 nmol/L), sufficient (12.6 nmol/L), and supplemented (301 nmol/L) cells in humans for 7 d. The efficacy of treatment was confirmed by assessing glutathione reductase activity and concentrations of reduced glutathione as markers of riboflavin status. LSD activity was 21% greater in riboflavin-supplemented cells compared with riboflavin-deficient and -sufficient cells. The loss of LSD activity was associated with a gain in the abundance of H3K4me2 marks in the albumin promoter; the abundance of H3K4me2 marks was ∼170% higher in riboflavin-deficient cells compared with sufficient and supplemented cells. The abundance of the repression mark, K9-trimethylated histone H3, was 38% lower in the albumin promoter of riboflavin-deficient cells compared with the other treatment groups. The expression of albumin mRNA was aberrantly increased by 200% in riboflavin-deficient cells compared with sufficient and supplemented cells. In conclusion, riboflavin deficiency impairs gene regulation by epigenetic mechanisms, mediated by a loss of LSD1 activity.

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Section: Introductionmentioning

confidence: 99%

Transcriptional Regulation of the Albumin Gene Depends on the Removal of Histone Methylation Marks by the FAD-Dependent Monoamine Oxidase Lysine-Specific Demethylase 1 in HepG2 Human Hepatocarcinoma Cells

Liu

Zempleni

2014

The Journal of Nutrition

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“…Investigations in this laboratory have focused upon the physiological consequences to riboflavin metabolism associated with the administration of tri-and tetracyclic drugs (7,(18)(19)(20). Each of these compounds when used in clinically relevant doses in laboratory animals diminishes the formation of FAD.…”

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confidence: 99%

Adriamycin-Induced Increase in Serum Aldosterone Levels: Effects in Riboflavin-Sufficient and Riboflavin-Deficient Rats*

et al. 1990

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Previous studies in rats have demonstrated that 1) aldosterone enhances biosynthesis of renal flavin coenzymes; 2) riboflavin analogs inhibit the synthesis of aldosterone; and 3) adriamycin inhibits flavin coenzyme biosynthesis. In their entirety, these findings suggest that both diminished flavin coenzyme biosynthesis induced by adriamycin and a dietary riboflavin deficiency would result in decreased formation of aldosterone. The present study examined the effects of adriamycin treatment on serum aldosterone in rats consuming either a diet adequate in riboflavin or a riboflavin-deficient diet. Groups of rats fed specially prepared diets were injected for 3 days with adriamycin (cumulative dose range, 6-24 mg/kg BW). Pair-fed controls were given saline. After death, adrenal glands were excised, and blood samples were analyzed for aldosterone levels. No changes in adrenal weights or protein and potassium concentrations were observed after adriamycin treatment. In contrast to initial predictions, in riboflavin-sufficient rats, serum aldosterone levels were markedly enhanced by adriamycin in a dose-related manner. Riboflavin-deficient animals had lower basal aldosterone levels and markedly attenuated responses to adriamycin than did riboflavin-sufficient rats. In separate groups of adriamycin-treated rats fed a normal chow diet, serum aldosterone levels increased, and serum corticosterone levels showed a small but significant decline. In addition, adriamycin treatment caused an increase in urinary potassium excretion and a decrease in sodium excretion. These results suggest that flavins play a decisive role in regulating the levels of aldosterone and raise the possibility that the adriamycin-induced increase in serum aldosterone may be part of the pathogenetic mechanisms of cardiovascular toxicity and overall muscular weakness.

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From Cholesterogenesis to Steroidogenesis: Role of Riboflavin and Flavoenzymes in the Biosynthesis of Vitamin D

Pinto

Cooper

2014

Advances in Nutrition

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Flavin-dependent monooxygenases and oxidoreductases are located at critical branch points in the biosynthesis and metabolism of cholesterol and vitamin D. These flavoproteins function as obligatory intermediates that accept 2 electrons from NAD(P)H with subsequent 1-electron transfers to a variety of cytochrome P450 (CYP) heme proteins within the mitochondria matrix (type I) and the (microsomal) endoplasmic reticulum (type II). The mode of electron transfer in these systems differs slightly in the number and form of the flavin prosthetic moiety. In the type I mitochondrial system, FAD-adrenodoxin reductase interfaces with adrenodoxin before electron transfer to CYP heme proteins. In the microsomal type II system, a diflavin (FAD/FMN)-dependent cytochrome P450 oxidoreductase [NAD(P)H-cytochrome P450 reductase (CPR)] donates electrons to a multitude of heme oxygenases. Both flavoenzyme complexes exhibit a commonality of function with all CYP enzymes and are crucial for maintaining a balance of cholesterol and vitamin D metabolites. Deficits in riboflavin availability, imbalances in the intracellular ratio of FAD to FMN, and mutations that affect flavin binding domains and/or interactions with client proteins result in marked structural alterations within the skeletal and central nervous systems similar to those of disorders (inborn errors) in the biosynthetic pathways that lead to cholesterol, steroid hormones, and vitamin D and their metabolites. Studies of riboflavin deficiency during embryonic development demonstrate congenital malformations similar to those associated with genetic alterations of the flavoenzymes in these pathways. Overall, a deeper understanding of the role of riboflavin in these pathways may prove essential to targeted therapeutic designs aimed at cholesterol and vitamin D metabolism.

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Inhibition of Riboflavin Metabolism in Cardiac and Skeletal Muscles of Rats by Quinacrine and Tetracycline

Cited by 3 publications

References 14 publications

Transcriptional Regulation of the Albumin Gene Depends on the Removal of Histone Methylation Marks by the FAD-Dependent Monoamine Oxidase Lysine-Specific Demethylase 1 in HepG2 Human Hepatocarcinoma Cells

Transcriptional Regulation of the Albumin Gene Depends on the Removal of Histone Methylation Marks by the FAD-Dependent Monoamine Oxidase Lysine-Specific Demethylase 1 in HepG2 Human Hepatocarcinoma Cells

Adriamycin-Induced Increase in Serum Aldosterone Levels: Effects in Riboflavin-Sufficient and Riboflavin-Deficient Rats*

From Cholesterogenesis to Steroidogenesis: Role of Riboflavin and Flavoenzymes in the Biosynthesis of Vitamin D

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