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Growth Disorders and Homocysteine Metabolism*

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Growth Disorders and Homocysteine Metabolism* A n n a l s o f C linical and Laboratory Science, Vol. 5, No. 3 Copyright © 1975, Institute for Clinical Science Growth Disorders and Homocysteine Metabolism* KILMER S. McCULLY, M.D. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 ABSTRACT Inherited disorders of homocysteine metabolism produce accelerated growth and arteriosclerosis with myointimal hyperplasia. The growth of cell cultures from cystathionine synthetase deficient inidividuals with homocystinuria is characterized by abnormal contact inhibition and production of an aggregated proteoglycan matrix which binds excess sulfate. Homocysteic acid, a precursor of sulfate ester, increases the growth rate of normal guinea pigs. Synthesis of homocysteic acid from homocysteine thiolactone is more rapid in the livers of young animals than adults, and hypophysectomy results in a pattern of homo­ cysteine thiolactone metabolism resembling that in liver of adult animals. Homocysteine thiolactone metabolism differs in guinea pig, an herbivorous species, and in rat, an omnivorous species. Sulfate binding by cultured human cells is slightly increased when homocysteic acid is present in the culture medium. These observations suggest a relationship between homocysteic acid and somatomedin, a serum polypeptide which mediates the action of growth hormone. The growth disorders associated with homocystinuria, including arteriosclerosis and accelerated growth, are believed to result from increased conversion of methionine to homocysteine thiolactone and homocysteic acid. Introduction mal hyperplasia and arteriosclerosis are Homocystine excretion was discovered found in arteries and arterioles of individ­ in mentally retarded children2’6 with ac­ uals with homocystinuria caused by each celerated growth, dislocated lenses, osteo­ of these enzyme deficiencies.12 The growth porosis, pectus deformities, hernias, light of cells cultured from the skin of individ­ colored hair and cardiovascular disease.17 uals with cystathionine synthetase defi­ Homocystinuria is associated with an in­ ciency is characterized by abnormal contact herited deficiency of one of three enzymes, inhibition and producton of an aggregated cystathionine synthetase,18 N5 methyltetra- proteoglycan matrix which binds more sul­ hydrofolate methyl transferase,19 and meth- fate than the fibrillar matrix of normal ylenetetrahydrofolate reductase.20 Myointi- cells.15 The sulfur of homocysteine thiolac­ tone is a precursor of phosphoadenosine * Supported by grants from the National Insti­ phosphosulfate and proteoglycan sulfate tutes of Health, AM-15978, CDA-HL-18747 and the American Heart Association, 73-655. ester in these cell cultures.14 Somatomedin,5 147 1 4 8 MCCULLY a serum polypeptide which increases sul­ styrene resin columns (Aminex A-6),f fate binding by cartilage fragments, is be­ using stepwise elution by citrate bufferf at lieved to mediate the physiological effects pH 3.25, 4.25 and 7.0 at 50°. Aliquots of of growth hormone.23 Because of these ob­ the fractions were counted in Bray’s solu­ servations, a relationship between homo­ tion,1 and the position of eluted radioactive cysteine metabolism and the physiological peaks was compared to that of authentic action of growth hormone was suggested.14 amino acids. The radioactive peaks were Homocysteic acid, the sulfonic acid de­ pooled, desalted on a 0.9 X 10 cm Dowex rivative of homocysteine, is a precursor of AG 50 X 8, 200-450 meshf column, eluted phosphoadenosine phosphosulfate and pro­ with 1.4 M NH4OH and lyophylized. The teoglycan sulfate ester.14 In order to inves­ residue was dissolved in H20 and chromat­ tigate the relationship between homocys­ ographed on silica gel TLC-TGF plates,£ teine metabolism and the physiological ac­ using butanolacetic acid—H20 (4:1:1 by tion of growth hormone, the conversion of volume), for comparison with authentic homocysteine thiolactone to homocysteic compounds. acid was compared in young, adult and Cells cultured from normal human skin hypophysectomized animals. The growth biopsies were maintained in Eagle’s min­ promoting activity of homocysteic acid was imal essential medium with 10 percent fetal determined by weight acquisition in nor­ calf serum, according to standard tech­ mal and scorbutic guinea pigs, and the niques. Equal numbers of cells were pas­ eifect of homocysteic acid on sulfate bind­ saged into media containing S5S04, 1 /xCi ing was studied in human cell cultures. per ml, 0.8 mM, and homocysteic acid and refed twice weekly. The cultures became Materials and Methods confluent after seven days, and half the cultures were incubated an additional ten The conversion of homocysteine thiolac­ days. The media were removed, and the tone to free amino acid derivatives was monolayer was rinsed with cold phosphate studied by injecting 5.0 ¿u.Ci of carboxyl-14C buffered saline, scraped into saline and 1-homocysteine thiolactone hydrochloride* homogenized. Radioactivity of the homog- with 7.5 mg dl-homocysteine thiolactone enate was determined, using Bray’s solu­ hydrochloride in 5 ml of normal saline tion, and protein was determined, using the intraperitoneally in guinea pigs or rats. Lowry method.11 After one hour the livers were removed, Three groups of six guinea pigs weighing rinsed with buffer, chilled, diced with 320 to 390 g were injected subcutaneously scissors and homogenized in a Waring every day for 22 days with 30 mg per kg blender for 20 to 30 seconds with two vol­ of neutralized homocysteic acid or an equi- umes of cold sucrose, KHC03, KC1 buffer8 molar quantity of saline. Initial mean containing 15 mg per 1 of thiodiglycol and weights were 347 to 357 g. The animals 0.5 g per 1 of ethylene diamine tetraacetic were fed chow* or an ascorbic acid defi­ acid (EDTA). The extract was decanted, cient diet.f Average growth rates, calcu­ deproteinized by adding excess sulfosali- lated from biweekly weights, were linear cylic acid and centrifuged at 10,000 g for during the experimental period. P values 15 minutes. Amino acids were separated by were calculated, using the student t test, standard techniques of amino acid chroma­ tography on 0.9 X 60 cm sulfonated poly­ | Malinckrodt. * Calbiochem. * Agway. f Bio-Rad. f Nutritional Biochemicals, Inc. GROWTH AND HOMOCYSTEINE f * ! 149 R esu lts T A B L E I A The conversion of homocysteine thiolac­ Metabolism of Homocysteine Thiolactone in Liver Percentage of 1I+C Recovered by Chromatography tone to free amino acids of liver was deter­ mined in young and adult guinea pigs, in Guinea Guinea Hypox P ig - P ig R a t R a t R a t rats and in hypophysectomized rats. 14C- Amino A cid (545 g ) (125 g ) (400 g ) (120 g ) (1 2 0 g ) carboxyl 1-homocysteine thiolactone was in­ jected intraperitoneally; after one hour, the Homocysteic 6.8 13.8 10.2 24.4 18.0 acid livers were homogenized, deproteinized Homocysteine 7.8 13.6 13.8 21.4 12.0 sulfinic acid and chromatographed on sulfonated poly­ Homocysteine 0.5 <0.1 20.3 16.3 23.0 styrene resin. The percentage of recovered Homocystine <0.1 <0.1 5.9 <1.0 7.0 Homocysteine 1.5 0.03 18.4 <1.0 6.7 14C is listed in table I for each free amino thiolactone Unidentified 78.1 68.6 27.8 34.6 31.2 acid recovered by chromatography. homocysteine derivatives (10) Cystathionine 5.4 3.3 3.1 <1.0 <1.0 The conversion of homocysteine thiolac­ Adenosyl <1.0 <1.0 <1.0 3.2 <1.0 tone to homocysteic acid and homocysteine homocysteine sulfinic acid in liver was greater in young, rapidly growing guinea pigs and rats than in adult animals. Only traces of unmetab- than in rat liver. Conversion of homocys­ olized homocysteine thiolactone were found teine thiolactone to multiple unidentified in young animals, whereas a large amount homocysteine derivatives was greater in was recovered from adult rat liver and a guinea pig than in rat liver. The sulfur of small amount from adult guinea pig liver. these unidentified derivatives is oxidized, Conversion of homocysteine thiolactone to since they all yielded homocysteic acid cystathionine was greater in adult than in when desalted, isolated, and chromato­ young animals. Decreased conversion of graphed on thin layers of silica gel. homocysteine thiolactone to homocysteic Three groups of six guinea pigs were acid and homocysteine sulfinic acid was injected subcutaneously once daily with found in hypophysectomized rat liver, com­ neutralized homocysteic acid or an equi- pared to the conversion found in liver of a molar quantity of saline. Weights were re­ young rat of the same size. corded twice weekly, and the final mean Considerable differences in homocysteine weights were compared (table II). The thiolactone metabolism were found in growth rates of the groups fed chow were guinea pigs compared to rats (table I). linear, as illustrated in figure 1. Larger amounts of homocysteine occurred Homocysteic acid increased the growth in rat liver, but only traces of homocysteine rate of normal young guinea pigs when were recovered from guinea pig liver. Ho­ given subcutaneously for 22 days in a dose mocystine was recovered from adult rat of 30 mg per kg per day (table II and liver and hypophysectomized rat liver but figure 1). A higher dose of 80 mg per kg not from adult guinea pig liver or from per day resulted in the same growth rate the liver of young animals of either species. as the lower dose, but the minimum dose The conversion of homocysteine thiolactone necessary to produce the effect was not to homocysteic acid and homocysteine sul­ determined. The guinea pigs given an
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