Growth Promotion by Homocysteic Acid

Clopath, P.; Smith, Virginia C.; McCully, Kilmer S.

doi:10.1126/science.1257770

Cited by 33 publications

(9 citation statements)

References 6 publications

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“…McCully (3) and Clopath et al (2) reported that HCA, a metabolite of HC, restored the growth of hypophysectomized rats and that serum from these animals contained somatomedin activity similar to that of control rats. They concluded that HCA acted like pituitary GH and that this explains the excessive Marked elevation in IGF-1 or IGFBP-3 was not observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

Influence of Metabolic Control on Growth in Homocystinuria due to Cystathionine B-Synthase Deficiency

2001

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The etiology of the tall stature almost invariably seen in homocystinuric patients is not known. The effect of metabolic control and the role of the GH-IGF system on growth were investigated in 10 patients with homocystinuria. There was a direct correlation between the plasma free homocyst(e)ine and growth velocity SD scores in 18 patient years (r, 0.46; p Ͻ 0.05). Plasma 2-y cumulative free homocyst(e)ine and height SD scores were directly correlated (r, 0.82; p Ͻ 0.01). Growth velocity SD scores were lower in patients with optimal metabolic control than in those with poorer control (Ϫ0.10 Ϯ 0.65 versus 0.95 Ϯ 0.68, p Ͻ 0.01). Height SD scores were also lower in the optimally controlled group (Ϫ0.01 Ϯ 0.81 versus 1.73 Ϯ 0.88, p Ͻ 0.05). GH and GH-related peptides did not deviate significantly from the reference ranges. These findings suggest that overgrowth is directly mediated by homocysteine, that the GH-IGF axis is not involved, and that it may be prevented by optimal metabolic control. Homocystinuria (McKusick 236200) due to cystathionine B-synthase (EC 4.2.1.22) deficiency is an inborn error of transsulfuration metabolism. The major biochemical abnormalities include elevation of HC and methionine and reduction of cystine in body fluids. Clinical manifestations include dislocation of the optic lens, mental retardation, psychiatric disturbances, thromboembolic phenomena, malar flush, livido reticularis, and skeletal abnormalities such as osteoporosis, scoliosis, arachnodactyly, and tall stature (1). It has been difficult to relate this wide variety of symptoms to a deficiency of a single enzyme. Thus, it has been classified as a connective tissue disorder, the result either of fibrillin damage or of impaired cross-linkage caused by complexing between aldehyde groups and HC. Although this may account for a number of the symptoms of the disease, it may not be responsible for the tall stature that has almost invariably been associated with the disease. Both HC and HCA, the sulfonic acid derivative of HC, have been suggested as the cause of the excessive growth. One study reported that HCA increased serum somatomedin activity in rats (2), whereas another study found that it accelerated the growth of guinea pigs (3). These findings have been challenged by other studies that have implicated HC as the agent responsible for growth (4,5). These studies have all been carried out either in animals or in cell lines derived from homocystinuric patients. However, the relationship of the growth pattern to the degree of metabolic control, as defined by the plasma HC, has not been evaluated in homocystinuric patients.Our interest in this excessive growth was stimulated by the observation that each of our patients diagnosed as the result of newborn screening and maintained in good metabolic control has grown at a rate similar to that of unaffected siblings, whereas patients diagnosed later in life have been excessively tall. In addition, the loss of metabolic control in several patients has precipitated a growth spurt. This l...

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Section: Discussionmentioning

confidence: 99%

Influence of Metabolic Control on Growth in Homocystinuria due to Cystathionine B-Synthase Deficiency

2001

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“…Together, the observed decrease in MAT and increase in betaine-homocysteine methyltransferase would also be effective in preventing the accumulation of homocysteine, which, as stated earlier, has not been detected in plasma or urine in this study. Protection against homocysteine accumulation may be of physiological significance since several studies have suggested that homocysteine is a potentially toxic metabolite of methionine, and has been implicated in such diverse conditions as abnormal acceleration of skeletal growth, myointimal hyperplasia (Gerritsen and Waisman 1972;Clopath et al 1975), schizophrenia (Beaton et al 1975), and coronary artery disease (Wilcken and Wilcken 1976).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Diet and of Methionine Loading on Activity of Enzymes in the Transulfuration Pathway in Sheep

Radcliffe¹,

Egan²

1978

Aust. Jnl. Of Bio. Sci.

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In three experiments, activity of hepatic enzymes associated with metabolism of methionine through the transulfuration pathway were studied with respect to possible effects of diet and methionine infusion per abomasum.In experiment 1 no differences in methionine adenosyltransferase (MAT) or cystathionine )I-lyase (CGL) were detected between lucerne and wheaten straw diets, or between effects of fasting for 48 and 96 h after feeding lucerne chaff as opposed to fasting after feeding wheaten straw. Fasting for 96 h resulted in a trend toward increasing CGL and MAT specific activities on both diets.In experiment 2 MAT was depressed significantly by infusion of methionine at 1·4 g/day and to a greater extent by infusion at 4·2 g/day, whilst CGL was not significantly affected.In experiment 3 MAT specific activity decreased significantly in response to both levels of methionine supplementation.Betaine-homocysteine methyltransferase activity was increased by methionine infusion. CGL decreased in all treatments but there was a larger decrease in those animals receiving methionine infusion. No significant changes were observed in relation to other enzymes examined which included cystathionine fi-synthase and threonine dehydratase. These observations are consistent with the hypothesis that in sheep the increase in methionine in blood plasma which occurs when methionine is absorbed in increased amounts may be due to reduced entry into the transulfuration pathway because of a repression of MAT activity.

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“…In experiments with hypophysectomized rats treated with thyroxine, homocysteic acid was demonstrated to stimulate tail growth and to increase the thickness of tibial epiphysis cartilage, assays for growth promotion (38). Serum somatomedin (IGF-1) activity, as determined by the porcine disk assay, was increased by homocysteic acid.…”

Section: Discovery Of Homocysteine Thiolactone Conversion To Sulfatementioning

confidence: 99%

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

McCully

2015

Comprehensive Physiology

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The importance of homocysteine in vascular function and arteriosclerosis was discovered by demonstration of arteriosclerotic plaques in children with homocystinuria caused by inherited enzymatic deficiencies of cystathionine synthase, methionine synthase, or methylene-tetrahydrofolate reductase. According to the homocysteine theory of arteriosclerosis, an elevated blood homocysteine level is an important risk factor for atherosclerosis in subjects without these rare enzymatic abnormalities. The homocysteine theory is supported by demonstration of arterial plaques in experimental animals with hyperhomocysteinemia, by discovery of a pathway for conversion of homocysteine thiolactone to sulfate in cell cultures from children with homocystinuria, and by demonstration of growth promotion by homocysteic acid in normal and hypophysectomized animals. Studies with cultured malignant cells revealed abnormal homocysteine thiolactone metabolism, resulting in homocysteinylation of proteins, nucleic acids, and glycosaminoglycans, explaining the abnormal oxidative metabolism, abnormalities of cellular membranes, and altered genetic expression observed in malignancy. Abnormal homocysteine metabolism in malignant cells is attributed to deficiency of thioretinamide, the amide synthesized from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide combine with cobalamin to form thioretinaco. Based on the molecular structure of thioretinaco, a theory of oxidative phosphorylation was proposed, involving oxidation to a disulfonium derivative by ozone, and binding of oxygen, nicotinamide adenine dinucleotide and phosphate as the active site of adenosine triphosphate synthesis in mitochondria. Obstruction of vasa vasorum by aggregates of microorganisms with homocysteinylated low-density lipoproteins is proposed to cause ischemia of arterial wall and a microabscess of the intima, the vulnerable atherosclerotic plaque.

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Growth Promotion by Homocysteic Acid

Cited by 33 publications

References 6 publications

Influence of Metabolic Control on Growth in Homocystinuria due to Cystathionine B-Synthase Deficiency

Influence of Metabolic Control on Growth in Homocystinuria due to Cystathionine B-Synthase Deficiency

The Effect of Diet and of Methionine Loading on Activity of Enzymes in the Transulfuration Pathway in Sheep

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

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