Betaine homocysteine methyltransferase: gene cloning and expression analysis in rat liver cirrhosis

Forestier, Marc; Bänninger, Reto; Reichen, Jürg; Solioz, Marc

doi:10.1016/s0925-4439(03)00037-1

Cited by 22 publications

(19 citation statements)

References 29 publications

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“…It has been shown that down-regulation of Bhmt and Cth impairs conversion of homocysteine to methionine and cysteine, respectively, resulting in increased homocysteine levels in the cell (Torres et al, 1999;Forestier et al, 2003). Homocysteine accumulation is associated with impaired liver function, necrosis, liver cirrhosis, and fibrogenesis (Torres et al, 1999;Finkelstein, 2003).…”

Section: Discussionmentioning

confidence: 99%

Comparison of Coumarin-Induced Toxicity between Sandwich-Cultured Primary Rat Hepatocytes and Rats in Vivo: A Toxicogenomics Approach

Kienhuis¹,

Wortelboer²,

Hoflack³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Sandwich-cultured primary rat hepatocytes are often used as an in vitro model in toxicology and pharmacology. However, loss of liver-specific functions, in particular, the decline of cytochrome P450 (P450) enzyme activity, limits the value of this model for prediction of in vivo toxicity. In this study, we investigated whether a hepatic in vitro system with improved metabolic competence enhances the predictability for coumarin-induced in vivo toxicity by using a toxicogenomics approach. Therefore, primary rat hepatocytes were cultured in sandwich configuration in medium containing a mixture of low concentrations of P450 inducers, phenobarbital, dexamethasone, and ␤-naphthoflavone. The toxicogenomics approach used enabled comparison of similar mechanistic endpoints at the molecular level between in vitro and in vivo conditions, namely, compound-induced changes in multiple genes and signaling pathways. Toxicant-induced cytotoxic effects and gene expression profiles observed in hepatocytes cultured in modified medium and hepatocytes cultured in standard medium (without inducers) were compared with results from a rat in vivo study. Coumarin was used as a model compound because its toxicity depends on bioactivation by P450 enzymes. Metabolism of coumarin toward active metabolites, coumarin-induced cytotoxicity, and gene expression modulation were more pronounced in hepatocytes cultured in modified medium compared with hepatocytes cultured in standard medium. In addition, more genes and biological pathways were similarly affected by coumarin in hepatocytes cultured in modified medium and in vivo. In conclusion, these experiments showed that for coumarin-induced toxicity, sandwich-cultured hepatocytes maintained in modified medium better represent the situation in vivo compared with hepatocytes cultured in standard medium.

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Section: Discussionmentioning

confidence: 99%

Comparison of Coumarin-Induced Toxicity between Sandwich-Cultured Primary Rat Hepatocytes and Rats in Vivo: A Toxicogenomics Approach

Kienhuis¹,

Wortelboer²,

Hoflack³

et al. 2006

Drug Metab Dispos

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“…This NO induced inactivation is related to its binding capacity to cobalt moiety of vitamin B12 (Danishpajooh et al, 2001;Brouwer et al, 1996). A recent report by Forestier et al demonstrated that the expression and activity of betaine homocysteine methyltransferase (BHMT) decrease in biliary cirrhosis (Forestier et al, 2003) and these further prevent the remethylation process. So, according to the mentioned evidences, there is a complex interaction between different factors, which can lead to decreased Hcy utilization.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine alterations in experimental cholestasis and its subsequent cirrhosis

et al. 2005

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“…Decreased BHMT mRNA and protein levels were observed in cirrhotic patients and animal models, the strongest effect being observed upon HCV [98,99].…”

Section: Pathological Implications Of Bhmtmentioning

confidence: 98%

Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism?

Pajares

Pérez‐Sala

2006

Cell. Mol. Life Sci.

171

108

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Betaine homocysteine methyltransferase (BHMT), a Zn(2+)-dependent thiolmethyltransferase, contributes to the regulation of homocysteine levels, increases in which are considered a risk factor for cardiovascular diseases. Most plasma homocysteine is generated through the liver methionine cycle, in which BHMT metabolizes approximately 25% of this non-protein amino acid. This process allows recovery of one of the three methylation equivalents used in phosphatidylcholine synthesis through transmethylation, a major homocysteine-producing pathway. Although BHMT has been known for over 40 years, the difficulties encountered in its isolation precluded detailed studies until very recently. Thus, the last 10 years, since the sequence became available, have yielded extensive structural and functional data. Moreover, recent findings offer clues for potential new functions for BHMT. The purpose of this review is to provide an integrated view of the knowledge available on BHMT, and to analyze its putative roles in other processes through interactions uncover to date.

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Betaine homocysteine methyltransferase: gene cloning and expression analysis in rat liver cirrhosis

Cited by 22 publications

References 29 publications

Comparison of Coumarin-Induced Toxicity between Sandwich-Cultured Primary Rat Hepatocytes and Rats in Vivo: A Toxicogenomics Approach

Comparison of Coumarin-Induced Toxicity between Sandwich-Cultured Primary Rat Hepatocytes and Rats in Vivo: A Toxicogenomics Approach

Homocysteine alterations in experimental cholestasis and its subsequent cirrhosis

Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism?

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