Glycine N-methyltransferase affects the metabolism of aflatoxin B1 and blocks its carcinogenic effect

Yen, Chia-Hung; Hung, Jan Jong; Ueng, Yune-Fang; Liu, Shih‐Ping; Chen, Shih Yin; Liu, Hsiao Han; Chou, Teh Ying; Tsai, Ting Fen; Darbha, Ramalakshmi; Hsieh, Ling Ling; Chen, Yi Ming Arthur

doi:10.1016/j.taap.2008.12.013

Cited by 36 publications

(42 citation statements)

References 34 publications

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“…In addition to binding with folate (48), it also interacts with environmental carcinogens, such as benzo(a)pyrene and aflatoxin B1, and inhibits DNA adduct formation (28,49). To our knowledge, this is the first report demonstrating that GNMT plays an important role in regulating cholesterol homeostasis via interaction with NPC2.…”

Section: Resultsmentioning

confidence: 86%

Glycine N-Methyltransferase Deficiency Affects Niemann-Pick Type C2 Protein Stability and Regulates Hepatic Cholesterol Homeostasis

Liao¹,

Chen²,

Lee³

et al. 2011

Mol Med

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Nonalcoholic fatty liver disease (NAFLD) is associated with the development of metabolic syndromes and hepatocellular carcinoma (HCC). Cholesterol accumulation is related to NAFLD, whereas its detailed mechanism is not fully understood. Previously, we reported that glycine N-methyltransferase (GNMT) knockout (Gnmt ings and coimmunoprecipitation assays elucidated that the C conserved region (81-105 amino acids) of NPC2 interacts with the carboxyl-terminal fragment (171-295 amino acids) of GNMT. Confocal microscopy demonstrated that when cells were treated with low-density lipoprotein, NPC2 was released from lysosomes and interacts with GNMT in the cytosol. Overexpression of GNMT doubled the half-lives of both NPC2 isoforms and reduced cholesterol accumulation in cells. Furthermore, GNMT was downregulated in the liver tissues from patients suffering with NAFLD as well as from mice fed a high-fat diet, high-cholesterol diet or methionine/choline-deficient diet. In conclusion, our study demonstrated that GNMT regulates the homeostasis of cholesterol metabolism, and hepatic cholesterol accumulation may result from downregulation of GNMT and instability of its interactive protein NPC2. Novel therapeutics for steatohepatitis and HCC may be developed by using this concept.

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Section: Resultsmentioning

confidence: 86%

Glycine N-Methyltransferase Deficiency Affects Niemann-Pick Type C2 Protein Stability and Regulates Hepatic Cholesterol Homeostasis

Liao¹,

Chen²,

Lee³

et al. 2011

Mol Med

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“…The AFB1 itself is not a potent toxin, and the bioactivation by liver CYP450 enzymes (Yen et al, 2009), particularly CYP3A4 and CYP1A2 to AFB1-8,9-epoxide, can form adducts with DNA and protein albumin (Partanen et al, 2010;Polychronaki et al, 2008), where its toxicity and carcinogenic effects are evident (Eaton and Gallagher, 1994). Although the AFB1 DNA adduct is more relevant with the HCC, we used AFB1 albumin adducts as biomarkers to assess the exposure.…”

Section: Discussionmentioning

confidence: 99%

How does airway exposure of aflatoxin B1 affect serum albumin adduct concentrations? Evidence based on epidemiological study and animal experimentation

Lai

Yang

et al. 2014

J. Toxicol. Sci.

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-Aflatoxin B1 (AFB1) airway inhalation represents an additional route of exposure to this toxin. However, the association between AFB1 inhalation and serum AFB1 albumin adducts remains unclear. The aim of this study was to explore the association between airway exposure to AFB1 and serum AFB1 albumin adduct concentrations via an epidemiological study, as well as in an AFB1 airway exposure animal model. Our epidemiological study was conducted in a sugar factory in the Guangxi Autonomous Region of China. In order to examine fungal contamination, air samples were obtained in the workshop and areas outside the workshop, such as the office and nearby store. Dust samples were also collected from the bagasse warehouse and presser workshop, and were analyzed using an indirect competitive enzyme-linked immunosorbent assay (ELISA). Additionally, blood samples were collected from a total of 121 workshop workers, and a control group (n = 80) was comprised of workers who undertook administrative tasks or other work outside the workshop. The animal experiment was conducted in the laboratory animal center of Guangxi Medical University, where a total of 60 adult male rabbits were involved in this study. By intubation, AFB1 was administered in three groups of rabbits daily, at dose rates of 0.075, 0.05 and 0.025 mg/kg/day for a period of 7 days. Blood samples were collected on day 1, day 3, day 7 and day 21, and the measurements of the AFB1 albumin adducts in the serum were performed by a double antibody sandwich ELISA. The epidemiological study showed that serum albumin adducts were detected in 67 workshop workers (55.37%), and the values ranged 6.4 pg/mg albumin to 212 pg/mg albumin (mean value: 51 ± 4.62 pg/mg albumin). In contrast, serum albumin adducts were detected in only 7 control group participants, with the values ranging from 9 pg AFB1/mg albumin to 59 pg/mg albumin (mean value: 20 ± 13.72 pg/mg albumin). The animal experiment revealed that the rabbits had detectable levels of AFB1 in their serum with a minimum effective dose of 0.05 mg/kg/day; while 11 of 17 (64.71%) rabbits had detectable levels of AFB1 albumin adducts in the high exposure group (0.075 mg/kg/day), and only 5 rabbits (26.32%) had detectable levels of AFB1 albumin adducts in the moderate exposure group (0.05 mg/kg/day). No rabbits had detectable levels of AFB1 albumin adducts in the low exposure group (0.025 mg/kg/day). Our results demonstrated that only exposure to a certain level of AFB1 would result in detectable levels of serum AFB1 albumin adducts. Interventional programs aimed at reducing exposure to AFB1 by inhalation are urgently needed in high-risk populations. Additional large-sample, well-designed randomized controlled trials are needed to further confirm our results.

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“…The GNMT transgene mouse model (GNMT tg ) was established by microinjecting the Friend leukemia virus B (FVB)-fertilized eggs that had been transfected with the pEGFP-GNMT vector containing full-length human GNMT cDNA as described previously (27). GNMT tg had a significant increase in GNMT protein in the liver compared with the WT mice during the early stage.…”

Section: Genetic Mouse Modelsmentioning

confidence: 99%

GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation

Wang

Lin

Liu³

et al. 2011

Mol Med

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Glycine N-methyltransferase (GNMT) is a major hepatic enzyme that converts S-adenosylmethionine to S-adenosylhomocysteine while generating sarcosine from glycine, hence it can regulate mediating methyl group availability in mammalian cells. GNMT is also a major hepatic folate binding protein that binds to, and, subsequently, may be inhibited by 5-methyltetrafolate. GNMT is commonly diminished in human hepatoma; yet its role in cellular folate metabolism, in tumorigenesis and antifolate therapies, is not understood completely. In the present study, we investigated the impacts of GNMT expression on cell growth, folate status, methylfolate-dependent reactions and antifolate cytotoxicity. GNMT-diminished hepatoma cell lines transfected with GNMT were cultured under folate abundance or restriction. Folate-dependent homocysteine remethylation fluxes were investigated using stable isotopic tracers and gas chromatography/mass spectrometry. Folate status was compared between wild-type (WT), GNMT transgenic (GNMT tg ) and GNMT knockout (GNMT ko ) mice. In the cell model, GNMT expression increased folate concentration, induced folate-dependent homocysteine remethylation, and reduced antifolate methotrexate cytotoxicity. In the mouse models, GNMT tg had increased hepatic folate significantly, whereas GNMT ko had reduced folate. Liver folate levels correlated well with GNMT expressions (r = 0.53, P = 0.002); and methionine synthase expression was reduced significantly in GNMT ko , demonstrating impaired methylfolate-dependent metabolism by GNMT deletion. In conclusion, we demonstrated novel findings that restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Studies on how GNMT expression impacts the distribution of different folate cofactors and the regulation of specific folate dependent reactions are underway.

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Glycine N-methyltransferase affects the metabolism of aflatoxin B1 and blocks its carcinogenic effect

Cited by 36 publications

References 34 publications

Glycine N-Methyltransferase Deficiency Affects Niemann-Pick Type C2 Protein Stability and Regulates Hepatic Cholesterol Homeostasis

Glycine N-Methyltransferase Deficiency Affects Niemann-Pick Type C2 Protein Stability and Regulates Hepatic Cholesterol Homeostasis

How does airway exposure of aflatoxin B1 affect serum albumin adduct concentrations? Evidence based on epidemiological study and animal experimentation

GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation

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