Deficiency of ornithine transcarbamylase (OTC; EC 2.1.3.3), a hepatic mitochondrial enzyme involved in the detoxification of ammonia, is a severe inborn error of metabolism. It is an X-linked disorder which results characteristically in ammonia intoxication, protein intolerance and mental retardation. Early death of affected hemizygous male infants is common, while clinical manifestations in heterozygous females are variable due to random X-chromosome inactivation. Prenatal diagnosis by amniocentesis has not been feasible because OTC is not expressed in amniocytes and because no unusual metabolites can be detected in amniotic fluid. Fetal liver biopsy has been performed for some families at risk, but the dangers inherent in this procedure severely limit its usefulness. In this report, we describe the use of a nearly full-length cloned human cDNA to begin to characterize normal and mutant human OTC genes. One of 15 affected males was found to have a partial deletion of the OTC gene. Two distinct restriction fragment length polymorphisms (RFLPs) were identified at the OTC locus using the restriction endonuclease MspI; 69% of women tested were heterozygous for one or both polymorphisms. Identification of these common polymorphisms makes it possible to offer prenatal diagnosis to a large fraction of obligate carriers and to provide information on carrier status to some females at risk.

Chromosome Deletion↗

PubMedDate not supplied

The molecular basis of cystinuria: an update.

Cystinuria is a hereditary disorder of cystine and dibasic amino acid transport across the luminal membrane of renal proximal tubule and small intestine. In 1992, a cDNA (rBAT) was isolated from kidney which induced high-affinity, sodium-independent uptake of cystine and dibasic amino acids when expressed in Xenopus oocytes. The rBAT gene was mapped to a region of chromosome 2p known to contain a cystinuria locus, and rBAT expression was demonstrated in the straight (S3) portion of renal proximal tubule and small intestine. Over 30 distinct rBAT mutations have been described in patients who inherit two fully recessive (type I) cystinuria genes. Recently, the second cystinuria gene (SLC7A9) on chromosome 19q was identified; SLC7A9 mutations were shown to cause the incompletely recessive form of cystinuria (types II and III). Patients who inherit two mutant SLC7A9 genes have recurrent nephrolithiasis comparable to those with two rBAT mutations. In some cystinuria families, patients inherit a fully recessive allele from one parent and an incompletely recessive allele from the other parent; patients with this 'mixed type' of cystinuria have somewhat milder disease. It is not yet clear whether this form of cystinuria involves rBAT as well as SLC7A9 mutations. Current evidence suggests that the transmembrane channel mediating uptake of cystine and dibasic amino acids at the luminal surface is encoded by SLC7A9; the smaller rBAT protein forms a heterodimeric complex with this channel and is critical for its targetting to the luminal membrane.

Amino Acid Transport Systems, Basic↗

PubMedDate not supplied

Formulation, development and characterization of sustained release varnishes containing amine and stannous fluorides.

This study describes properties of potential sustained release varnishes (SRV) containing amine fluoride or amine fluoride with stannous fluoride. The release kinetics, antibacterial properties and antiadhesion properties of two potential varnishes were tested. The varnish of ethylcellulose matrix was found to release fluoride for 4 h in vitro, while the formulation based on hydroxypropylmethylcellulose acetate succinate had a rapid release rate. Hydroxyapatite tablets coated with ethylcellulose-based SRV increased adhesion of Streptococcus mutans, while tablets coated with hydroxypropylmethylcellulose acetate succinate-based SRV decreased bacterial adhesion. Both types of SRV demonstrated a strong antibacterial effect on bacteria in biofilm.

Amines↗

PubMedDate not supplied

Loss of heterozygosity of methylenetetrahydrofolate reductase in colon carcinomas.

Folate derivatives are essential for DNA synthesis and methylation. A large proportion of the Caucasian population is heterozygous for a common substitution, 677C-->T (alanine-->valine), in methylenetetrahydrofolate reductase (MTHFR), an enzyme of folate interconversion. Homozygous mutant individuals, approximately 10-15% of North Americans, have been reported to have a reduced risk of colorectal cancer. We examined lymphocyte and tumor tissue DNA from colorectal carcinoma patients from two different populations to assess loss of heterozygosity (LOH) of MTHFR. We observed LOH in approximately 16% of colorectal tumors; in 8 of the 11 tumors with LOH, the mutant valine allele was lost. Additional studies are required to determine if preferential loss of the mutant allele is a common finding that could contribute to colorectal tumorigenesis.

Alleles↗

PubMedDate not supplied

[Identification of alpha-2 adrenergic receptors in rabbit adipocytes].

Adrenaline, an alpha and beta adrenergic agonist don't modify theophylline induced lipolysis in perirenal and epididymal adipose tissue of the rabbit. Clonidine an alpha 2 adrenergic agonist inhibits theophylline stimulated lipolysis in the two tissue indicating the existence of alpha 2 adrenergic responsiveness. Direct identification of these receptors by radioligand binding studies shows that (H3) yohimbine an alpha 2 adrenergic antagonist binds to rabbit's fat cell membranes with high affinity: KD = 1.7 +/- 0.1 nmoles. The maximal number of binding sites at saturation is low 16 +/- 29 fmoles/mg protein.

Adipose Tissue↗

PubMedDate not supplied

Oleate metabolism and endogenous triacylglycerol hydrolysis in isolated hepatocytes from rats fed a high-fat diet.

In isolated hepatocytes of fat-fed rats, as compared to control fed animals, the cellular uptake of [1-14C] oleate and its oxidation to CO2 were similar but the incorporation of the label into water-soluble products (mainly ketone bodies) was increased by 36.6% whereas its esterification to triacylglycerols and phospholipids decreased by 36%. While endogenous ketogenesis was slightly but not significantly increased, ketone body synthesis from both 2 mM octanoate and 0.7 mM oleate was stimulated two fold. Thus, in the fatfed rats the oxidative pathway is clearly activated whereas long chain fatty acids are preferentially channelled into the oxidation pathway at the expense of esterification. Yet, hepatocyte triacylglycerol content was 3-fold higher after fat-feeding. In this regard, lysosomal triacylglycerol lipase (EC 3.1.1.3) activity, in homogenates of hepatocytes was decreased by 32% (p less than 0.01). This findings suggest a lower breakdown of endogenous triacylglycerols, which, taken together with decreased secretion of VLDL lipoprotein triacylglycerol (Kalopissis et al. Biochem. J. 198: 373, 1981) and an in vivo increased fatty acid influx to the liver may contribute to the accumulation of lipids in the livers of fat-fed rats.

Animals↗

PubMedDate not supplied

[Influence of lactate and pyruvate on glucose absorption in vitro by the everted rat intestine].

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Animals↗