Taurine alleviates repression of betaine‐homocysteine S‐methyltransferase and significantly improves the efficacy of long‐term betaine treatment in a mouse model of cystathionine β‐synthase–deficient homocystinuria

Maclean, Kenneth N.; Jiang, Hua; Phinney, Whitney N; Keating, Amy K.; Hurt, K. Joseph; Stabler, Sally P.

doi:10.1096/fj.201802069rr

Cited by 12 publications

(13 citation statements)

References 70 publications

(103 reference statements)

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“…Thus it seems unlikely that either low choline or low taurine levels by themselves could be causing liver failure, although it is possible that there may be some sort of synergy between the two pathways. Consistent with our observations, adult HO mice have also been reported to show reductions in liver phosphocholine and betaine concentrations as well 40,41 …”

Section: Resultssupporting

confidence: 92%

Analysis of differential neonatal lethality in cystathionine β‐synthase deficient mouse models using metabolic profiling

et al. 2021

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Cystathionine beta‐synthase (CBS) is a key enzyme of the trans‐sulfuration pathway that converts homocysteine to cystathionine. Loss of CBS activity due to mutation results in CBS deficiency, an inborn error of metabolism characterized by extreme elevation of plasma total homocysteine (tHcy). C57BL6 mice containing either a homozygous null mutation in the cystathionine β‐synthase (Cbs−/−) gene or an inactive human CBS protein (Tg‐G307S Cbs−/−) are born in mendelian numbers, but the vast majority die between 18 and 21 days of age due to liver failure. However, adult Cbs null mice that express a hypomorphic allele of human CBS as a transgene (Tg‐I278T Cbs−/−) show almost no neonatal lethality despite having serum tHcy levels similar to mice with no CBS activity. Here, we characterize liver and serum metabolites in neonatal Cbs+/−, Tg‐G307S Cbs−/−, and Tg‐I278T Cbs−/− mice at 6, 10, and 17 days of age to understand this difference. In serum, we observe similar elevations in tHcy in both Tg‐G307S Cbs−/− and Tg‐I278T Cbs−/− compared to control animals, but methionine is much more severely elevated in Tg‐G307S Cbs−/− mice. Large scale metabolomic analysis of liver tissue confirms that both methionine and methionine‐sulfoxide are significantly more elevated in Tg‐G307S Cbs−/− animals, along with significant differences in several other metabolites including hexoses, amino acids, other amines, lipids, and carboxylic acids. Our data are consistent with a model that the neonatal lethality observed in CBS‐null mice is driven by excess methionine resulting in increased stress on a variety of related pathways including the urea cycle, TCA cycle, gluconeogenesis, and phosphatidylcholine biosynthesis.

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Section: Resultssupporting

confidence: 92%

Analysis of differential neonatal lethality in cystathionine β‐synthase deficient mouse models using metabolic profiling

et al. 2021

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“…Since no differences were observed in betaine and DMG urinary excretion between pnrCBS and cblC (data not shown), these lower ratios for DMG could suggest a lower or slower catabolization of betaine at the highest dosage through the BHMT in pnrCBS vs in cblC. A lower or slower betaine catabolization could be due to a decrease in mRNA and protein expression associated with a lower enzyme activity of BHMT; such decreases has been observed in various mouse models of CBS deficiency compared to wild-type mice [ 35 – 37 ]. This decrease in BHMT expression and activity has been linked to the hypermethioninemia observed in pnrCBS that could increase oxidative stress by reducing cysteine and glutathione production [ 37 ].…”

Section: Discussionmentioning

confidence: 91%

Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial

Imbard

Toumazi

Magréault

et al. 2022

Orphanet J Rare Dis

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Background Betaine is an “alternate” methyl donor for homocysteine remethylation catalyzed by betaine homocysteine methyltransferase (BHMT), an enzyme mainly expressed in the liver and kidney. Betaine has been used for more than 30 years in pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) and cobalamin C (cblC) deficiencies to lower the hyperhomocysteinemia, although little is known about the optimal therapeutic dosage and its pharmacokinetic in these patients. Aims We compared 2 betaine doses (100 mg/kg/day vs. 250 mg/kg/day) in children affected by pnrCBS or cblC deficiencies. We also measured the pharmacokinetics parameters after a single dose of betaine (100 or 250 mg/kg) in these patients. Methods We conducted a prospective, randomized, crossover clinical trial with blinded evaluation. The primary outcome was the equivalence of total plasma homocysteine (tHcy) concentrations upon one-month oral treatment with betaine at 100 versus 250 mg/kg/day. Results Eleven patients completed the study (5 pnrCBS and 6 cblC). tHcy concentrations were equivalent after a one-month treatment period for the two betaine dosages. Multivariate analysis showed a significant effect of betaine dose on methionine (Met) (p = 0.01) and S-adenosylmethionine (SAM) concentrations (p = 0.006). Conclusions Our analysis shows that there is no overt benefit to increasing betaine dosage higher than 100 mg/kg/day to lower tHcy concentrations in pnrCBS and cblC deficiencies. However, increasing betaine up to 250 mg/kg/d could benefit cblC patients through the increase of methionine and SAM concentrations, as low Met and SAM concentrations are involved in the pathophysiology of this disease. In contrast, in pnrCBS deficiency, betaine doses higher than 100 mg/kg/day could be harmful to these patients with pre-existing hypermethioninemia. Trial registration: Clinical Trials, NCT02404337. Registered 23 May 2015—prospectively registered, https://clinicaltrials.gov.

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“…This study did not replicate previously reported changes in cholesterol or ApoA1 levels, however, our study did find an intriguing association between elevated Lp(a) levels and thromboembolic events, which will require validation in a much larger study. Taurine appeared to provide some increased BHMT activity as evidence by increased dimethylglycine levels, its endproduct, but, in contrast to the mouse model, was not sufficient to lower homocysteine or raise methionine …”

Section: Discussionmentioning

confidence: 94%

“…Given the taurine‐related derepression of betaine‐homocysteine methytransferase (BHMT) in the homocystinuric mice, we evaluated patients treated with betaine . In these patients, high dose taurine treatment increased end‐product dimethylglycine (p = 0.05, increased in seven of nine patients), but without significant changes in homocysteine or methionine.…”

Section: Resultsmentioning

confidence: 99%

Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine β‐synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial

Hove

Freehauf

Fıçıcıoğlu

et al. 2019

J of Inher Metab Disea

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Study Objective: A phase 1/2 clinical trial was performed in individuals with cystathionine β synthase (CBS) deficient homocystinuria with aims to: (a) assess pharmacokinetics and safety of taurine therapy, (b) evaluate oxidative stress, inflammation, and vascular function in CBS deficiency, and (c) evaluate the impact of short-term taurine treatment. Methods: Individuals with pyridoxine-nonresponsive CBS deficiency with homocysteine >50 μM, without inflammatory disorder or on antioxidant therapy were enrolled. Biomarkers of oxidative stress and inflammation, endothelial function (brachial artery flow-mediated dilation [FMD]), and disease-related metabolites obtained at baseline were compared to normal values. While maintaining current Johan L. K. Van Hove and Cynthia L. Freehauf contributed equally to this study. Lucienne Driskill Foundation; William R. Hummel Homocystinuria Research Fund treatment, patients were treated with 75 mg/kg taurine twice daily, and treatment response assessed after 4 hours and 4 days. Results: Fourteen patients (8-35 years; 8 males, 6 females) were enrolled with baseline homocysteine levels 161 ± 67 μM. The study found high-dose taurine to be safe when excluding preexisting hypertriglyceridemia. Taurine pharmacokinetics showed a rapid peak level returning to near normal levels at 12 hours, but had slow accumulation and elevated predosing levels after 4 days of treatment. Only a single parameter of oxidative stress, 2,3-dinor-8-isoprostaglandin-F2α, was elevated at baseline, with no elevated inflammatory parameters, and no change in FMD values overall. Taurine had no effect on any of these parameters. However, the effect of taurine was strongly related to pretreatment FMD values; and taurine significantly improved FMD in the subset of individuals with pretreatment FMD values <10% and in individuals with homocysteine levels >125 μM, pertinent to endothelial function. Conclusion: Taurine improves endothelial function in CBS-deficient homocystinuria in patients with preexisting reduced function. K E Y W O R D Sclinical trial, endothelial function, homocystinuria, inflammation, oxidative stress, taurine

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Taurine alleviates repression of betaine‐homocysteine S‐methyltransferase and significantly improves the efficacy of long‐term betaine treatment in a mouse model of cystathionine β‐synthase–deficient homocystinuria

Cited by 12 publications

References 70 publications

Analysis of differential neonatal lethality in cystathionine β‐synthase deficient mouse models using metabolic profiling

Analysis of differential neonatal lethality in cystathionine β‐synthase deficient mouse models using metabolic profiling

Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial

Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine β‐synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial

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