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Deletion of a xenobiotic metabolizing gene in mice affects folate metabolism.

Wakefield L, Cornish V, Long H, Griffiths WJ, Sim E - Biochem. Biophys. Res. Commun. (2007)

Bottom Line: In vitro assays have suggested an endogenous role for human NAT1 in folate metabolism, but in vivo evidence to support this hypothesis has been lacking.These results support an in vivo role for mouse Nat2/human NAT1 in folate metabolism.In addition, effects of the Nat2 deletion on sex ratios and neural tube development are described.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.

ABSTRACT
The mouse arylamine N-acetyltransferase 2 (Nat2) and its homologue (NAT1) in humans are known to detoxify xenobiotic arylamines and are also thought to play a role in endogenous metabolism. Human NAT1 is highly over-expressed in estrogen receptor positive breast tumours and is implicated in susceptibility to neural tube defects. In vitro assays have suggested an endogenous role for human NAT1 in folate metabolism, but in vivo evidence to support this hypothesis has been lacking. Mouse Nat2 provides a good model to study human NAT1 as it shows similar expression profiles and substrate specificities. We have generated transgenic mice lacking a functional Nat2 gene and compared the urinary levels of acetylated folate metabolite para-aminobenzoylglutamate in Nat2 knockout and Nat2 wild-type mice. These results support an in vivo role for mouse Nat2/human NAT1 in folate metabolism. In addition, effects of the Nat2 deletion on sex ratios and neural tube development are described.

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Wholemount views of embryos showing neural tube defects. Embryos derived by crossing C57Bl/6 Nat2+/+ and Nat2−/− mice, and harvested at e10.5–e11.5. (A) Normal embryo (e11.5) viewed from right hand side. (B) Embryo (e11.5) with neural tube defect, showing incomplete closure of the anterior neuropore, viewed from right hand side in main panel; inset, dorsal view. (C) Embryo (e10.5) with neural tube defect at cervical level, viewed from right in main panel; inset, dorsal view. Arrowheads point to regions of incomplete closure of the neural tube. The orientation of the embryos is indicated in dorsal views; C, caudal; R, rostral.
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fig2: Wholemount views of embryos showing neural tube defects. Embryos derived by crossing C57Bl/6 Nat2+/+ and Nat2−/− mice, and harvested at e10.5–e11.5. (A) Normal embryo (e11.5) viewed from right hand side. (B) Embryo (e11.5) with neural tube defect, showing incomplete closure of the anterior neuropore, viewed from right hand side in main panel; inset, dorsal view. (C) Embryo (e10.5) with neural tube defect at cervical level, viewed from right in main panel; inset, dorsal view. Arrowheads point to regions of incomplete closure of the neural tube. The orientation of the embryos is indicated in dorsal views; C, caudal; R, rostral.

Mentions: We have tested whether Nat2 genotype influences susceptibility to neural tube defects, using the C57Bl/6 strain, which is not prone to neural tube defects, and scoring embryos for neural tube defects at e10.5 and e11.5. Amongst Nat2−/− offspring derived by incrossing, out of 64 embryos examined, only one embryo was observed to have a neural tube defect. To investigate the effects of an imbalance in parental Nat2 phenotype, crosses were set up using Nat2+/+ and Nat2−/− parents, generating Nat2+/− offspring. The incidence of neural tube defects amongst Nat2+/− offspring derived in this way was 14% (4/28). In three out of the four cases described in here, associated with the Nat2 allele, the position of the defect is caudal to the hindbrain, at the cervical level (Fig. 2).


Deletion of a xenobiotic metabolizing gene in mice affects folate metabolism.

Wakefield L, Cornish V, Long H, Griffiths WJ, Sim E - Biochem. Biophys. Res. Commun. (2007)

Wholemount views of embryos showing neural tube defects. Embryos derived by crossing C57Bl/6 Nat2+/+ and Nat2−/− mice, and harvested at e10.5–e11.5. (A) Normal embryo (e11.5) viewed from right hand side. (B) Embryo (e11.5) with neural tube defect, showing incomplete closure of the anterior neuropore, viewed from right hand side in main panel; inset, dorsal view. (C) Embryo (e10.5) with neural tube defect at cervical level, viewed from right in main panel; inset, dorsal view. Arrowheads point to regions of incomplete closure of the neural tube. The orientation of the embryos is indicated in dorsal views; C, caudal; R, rostral.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2315789&req=5

fig2: Wholemount views of embryos showing neural tube defects. Embryos derived by crossing C57Bl/6 Nat2+/+ and Nat2−/− mice, and harvested at e10.5–e11.5. (A) Normal embryo (e11.5) viewed from right hand side. (B) Embryo (e11.5) with neural tube defect, showing incomplete closure of the anterior neuropore, viewed from right hand side in main panel; inset, dorsal view. (C) Embryo (e10.5) with neural tube defect at cervical level, viewed from right in main panel; inset, dorsal view. Arrowheads point to regions of incomplete closure of the neural tube. The orientation of the embryos is indicated in dorsal views; C, caudal; R, rostral.
Mentions: We have tested whether Nat2 genotype influences susceptibility to neural tube defects, using the C57Bl/6 strain, which is not prone to neural tube defects, and scoring embryos for neural tube defects at e10.5 and e11.5. Amongst Nat2−/− offspring derived by incrossing, out of 64 embryos examined, only one embryo was observed to have a neural tube defect. To investigate the effects of an imbalance in parental Nat2 phenotype, crosses were set up using Nat2+/+ and Nat2−/− parents, generating Nat2+/− offspring. The incidence of neural tube defects amongst Nat2+/− offspring derived in this way was 14% (4/28). In three out of the four cases described in here, associated with the Nat2 allele, the position of the defect is caudal to the hindbrain, at the cervical level (Fig. 2).

Bottom Line: In vitro assays have suggested an endogenous role for human NAT1 in folate metabolism, but in vivo evidence to support this hypothesis has been lacking.These results support an in vivo role for mouse Nat2/human NAT1 in folate metabolism.In addition, effects of the Nat2 deletion on sex ratios and neural tube development are described.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.

ABSTRACT
The mouse arylamine N-acetyltransferase 2 (Nat2) and its homologue (NAT1) in humans are known to detoxify xenobiotic arylamines and are also thought to play a role in endogenous metabolism. Human NAT1 is highly over-expressed in estrogen receptor positive breast tumours and is implicated in susceptibility to neural tube defects. In vitro assays have suggested an endogenous role for human NAT1 in folate metabolism, but in vivo evidence to support this hypothesis has been lacking. Mouse Nat2 provides a good model to study human NAT1 as it shows similar expression profiles and substrate specificities. We have generated transgenic mice lacking a functional Nat2 gene and compared the urinary levels of acetylated folate metabolite para-aminobenzoylglutamate in Nat2 knockout and Nat2 wild-type mice. These results support an in vivo role for mouse Nat2/human NAT1 in folate metabolism. In addition, effects of the Nat2 deletion on sex ratios and neural tube development are described.

Show MeSH
Related in: MedlinePlus