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Qiao, Mu. / "June 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 190-209). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

This thesis describes a study on the impact of selected nutrients, growth hormones and in vivo genome stability on breast cancer risk in BRCA1 or BRCA2 germline mutation carriers. Peripheral blood lymphocyes of BRCA germline mutation carriers and healthy non-carrier controls were studied for the impact of folic acid deficiency on genome damage and the methionine-dependence phenotype (MDP; in combination with common polymorphisms in one-carbon metabolism) on breast cancer risk, respectively. Plasma IGF-1 and IGFBP-3 were determined and chromosome 17 aneuploidy and Her2 amplification were assessed in mononucleated lymphocytes to establish the association of these markers on breast cancer risk in BRCA germline mutation carriers, independently or in combination with plasma folate, vitamin B12, homocysteine, selenium and common gene variants in the one-carbon metabolism, DNA repair genes or glutathionine S-transferase.

Methylenetetrahydrofolate reductase (MTHFR), an important enzyme in folate metabolism, mediates the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate which serves as the carbon donor for the conversion of homocysteine to methionine. It is also inhibited by S-adenosylmethionine which has shown to be actively demethylated to form S-adenosylhomocysteine, which is hydrolysed to homocysteine. MTHFR deficiency exhibits well-documented clinical and biochemical symptoms. The human MTHFR cDNA was isolated by Goyette et al (1994), and fifteen mutations have been identified at this locus. / An animal model would prove to be useful for designing therapeutic approaches for understanding the pathogenesis of this genetic disease at the molecular level. The mouse MTHFR gene and cDNA have been isolated and partially characterized. Four genomic clones were isolated by library screening. One of these clones (clone 3) contained the 5$ sp prime$ end of the gene and was completely characterized. The clone was shown to have no rearrangements and is to be used to design targeting vectors for 'knockout mice' and mice carrying a common mutation which has been postulated to be a genetic risk factor for cardiovascular disease. The other three clones contain the remaining 3$ sp prime$ portion of the gene. The coding portion has approximately 90% homology with the human cDNA and also shows a similar gene structure. / A 2.2 Kb mouse MTHFR cDNA was isolated by library screening and was found to contain a 320 base pair extension at the 5$ sp prime$ end which has not been found in the human cDNA. The cDNA contains exons -1 -3, but also contains two possibly unspliced introns. A portion of this cDNA can however still be used to rescreen libraries to isolate a full length cDNA. The above research is the first genetic data on the mouse MTHFR gene and provides the basis for future research involving mouse models of MTHFR deficiency.

We have studied the effect of S-adenosylmethionine (SAM) on tail flick latency in the rat. We also studied the effect of methionine the immediate precursor of SAM. Administration of methionine to the rat increases brain SAM, but little is known about its behavioral effects. Long-Evans rats were given SAM and methionine orally at different doses and tail-flick latency was measured at various times. Both methionine and SAM increased tail-flick latency, but methionine did so at a lower dose. A biochemical study showed that methionine was more effective than SAM in raising brain SAM probably because it is transported better into brain. The biochemical measurements were not consistent with the idea that the effects of SAM and methionine were mediated by an increase in brain 5-HT. / Folate deficiency can lower brain SAM levels and cause depression. Thus, methionine, which raises brain SAM, may overcome the effects of folate deficiency. Seven day food records were done by 26 psychiatric outpatients who were stable on lithium treatment. Eight patients had mean daily folate intakes below those recommended. Some of those with low folate intake had high methionine intake consistent with the idea that methionine could substitute metabolically for folate deficiency. Daily methionine intakes ranged from 13 to 304% of the recommended intake. As methionine had behavioral effects in the rat at doses much less than the daily dietary intake this raises the question of whether varying daily intakes of methionine in humans have behavioral implications. (Abstract shortened by UMI.)

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Thesis (M.Sc.). / Written for the Dept. of Animal Science. Title from title page of PDF (viewed 2009/07/07). Includes bibliographical references.

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