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PubMedDate not supplied

Disposition in humans of racemic picenadol, an opioid analgesic.

Racemic picenadol is being tested clinically as an analgesic. The (+)-enantiomer of picenadol is an opioid agonist and the (-)-enantiomer is a weak agonist/antagonist. The disposition of racemic [14C] picenadol was studied in healthy men after a single dose was administered im (N = 3) and orally (N = 5). After the dose, virtually none of the radioactivity that appeared in blood was associated with the red cells. In plasma, approximately 4% of the radioactivity was attributable to the parent drug, the remainder being picenadol glucuronide (approximately 35%) and other metabolites. The t1/2 for total radioactivity was 6 hr, that for the unchanged drug was 3.5 hr. Picenadol was present in plasma almost exclusively as the (+)-enantiomer. However, after incubation with glucuronidase and sulfatase, plasma contained 2 to 4 times more (-)- than (+)-picenadol, indicating that more conjugated (-)-picenadol than conjugated (+)-picenadol was in the plasma. After im and oral administration of [14C]picenadol, plasma levels of radioactivity were generally 10 and 70 times higher than those in saliva, respectively. More than 90% of the administered radioactivity was excreted in the urine, mostly as picendol glucuronide, and lesser amounts of picenadol sulfate and N-desmethylpicenadol sulfate. Only about 1% of the administered dose of picenadol appeared unchanged in urine. The disposition of racemic picenadol in humans was stereoselective, the (-)-picenadol apparently being metabolized preferentially over the (+)-enantiomer. This finding was of particular interest in view of the dissimilar pharmacologic activities of the enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

beta-Glucuronide and sulfate conjugation of scopolamine and glycopyrrolate.

The metabolism of scopolamine and glycopyrrolate was studied in 11 healthy parturients undergoing cesarean section. After a single intramuscular injection of scopolamine (5 micrograms/kg, n = 7) or glycopyrrolate (6 micrograms/kg, n = 4), the concentrations of the drugs in the urine were determined up to 8-12 h using a radioreceptor assay. This assay measures scopolamine and glycopyrrolate with their possible active metabolites. The effect of beta-glucuronidase and sulfatase incubation on the drug concentrations was also studied. The concentrations of scopolamine and/or its active metabolites were on the average 7 times higher after incubation indicating that beta-glucuronide or sulfate conjugation is an important metabolic pathway for scopolamine. On the contrary, the glycopyrrolate concentrations increased only slightly between 1 and 3 hours after the drug injection. Thus, beta-glucuronide or sulfate conjugation plays only a minor part in the metabolism of glycopyrrolate.

Female↗
PubMed1990

[Biochemical diagnosis of rare hereditary metabolic disorders. Experiences from a patient sample of the Innsbruck University Pediatric Clinic 1984-1987].

The diagnosis of inherited metabolic diseases requires an intensive cooperation between the clinician, the clinical chemist and the biochemist to select patients for an adequate screening program, to avoid unnecessary expensive investigations and to achieve a final molecular diagnosis. Often a cooperation with specialized laboratories even in different countries is necessary. 29 patients with an inherited metabolic disorder have been evaluated at the Children's Hospital, University of Innsbruck, between 1984 and 1987. Seven patients with a disturbance in carbohydrate metabolism incl. pyruvate oxidation, nine with a defect in amino or organic acid metabolism, eleven patients with a lysosomal storage disorder, one patient with steroid-sulfatase deficiency and one with M. Wilson have been found. In nine of these 29 patients an organic aciduria was detected, four of them had lactic aciduria due to a mitochondrial defect of the oxidative energy metabolism. 21 children corresponded to a well-known classic phenotype, eight represented very rare or unique, not previously described clinical forms of a disease. In one third of the cases a cooperation with a foreign institute was necessary. The presentation of the most important biochemical investigations in children with inherited metabolic defects should give a survey of the diagnosis of such patients at a pediatric centre and should furthermore stimulate the development of a common diagnostic procedure program and the cooperation and coordination of the laboratories involved in the diagnosis of inherited metabolic disorders in Austria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1989

[Ichthyosis linked to the X chromosome. Biochemical and endocrinologic study].

The case of a 6-year-old male patient suffering from X-chromosome-linked ichthyosis is presented. There was no steroid sulfatase activity in the proband's leucocytes and cutaneous fibroblasts. The activity was decreased in the proband's mother's leucocytes and in one brother, affected by a mild ichthyosis. Basal plasma levels of dehydroepiandrosterone and its sulfate were normal for the patient's age, suggesting that sulfates do not play a significant role in the production of free steroids. After 3 intramuscular injections of 1,500 units of human chorionic gonadotropin, plasma levels of testosterone increased normally, indicating that there was no associated primary gonadal insufficiency.

Child↗
PubMed1989

Cloning and expression of human arylsulfatase A.

A full length cDNA for human arylsulfatase A was cloned and sequenced. The predicted amino acid sequence comprises 507 residues. A putative signal peptide of 18 residues is followed by the NH2-terminal sequence of placental arylsulfatase A. One of the arylsulfatase A peptides ends 3 residues ahead of the predicted COOH terminus. This indicates that proteolytic processing of arylsulfatase A is confined to the cleavage of the signal peptide. The predicted sequence contains three potential N-glycosylation sites, two of which are likely to be utilized. The sequence shows no homology to any of the known sequences of lysosomal enzymes but a 35% identity to human steroid sulfatase. Transfection of monkey and baby hamster kidney cells resulted in an up to 200-fold increase of the arylsulfatase A activity. The arylsulfatase A was located in lysosome-like structures and transported to dense lysosomes in a mannose 6-phosphate receptor-dependent manner. The arylsulfatase A cDNA hybridizes to 2.0- and 3.9-kilobase species in RNA from human fibroblasts and human liver. RNA species of similar size were detected in metachromatic leukodystrophy fibroblasts of two patients, in which synthesis of arylsulfatase A polypeptides was either detectable or absent.

Amino Acid Sequence↗
PubMed1989

An Xp22 microdeletion associated with ocular albinism and ichthyosis: approximation of breakpoints and estimation of deletion size by using cloned DNA probes and flow cytometry.

Ocular albinism of the Nettleship-Falls type (OA1) and X-linked ichthyosis (XI) due to steroid sulfatase (STS) deficiency are cosegregating in three cytogenetically normal half-brothers. The mother has patchy fundal hypopigmentation consistent with random X inactivation in an OA1 carrier. Additional phenotypic abnormalities that have been observed in other STS "deletion syndromes" are not present in this family. STS is entirely deleted on Southern blot in the affected males, but the loci MIC2X, DXS31, DXS143, DXS85, DXS43, DXS9, and DXS41 are not deleted. At least part of DXS278 is retained. Flow cytometric analysis of cultured lymphoblasts from one of the XI/OA1 males and his mother detected a deletion of about 3.5 million bp or about 2% of the X chromosome. Southern blot and RFLP analysis in the XI/OA1 family support the order tel-[STS-OA1-DXS278]-DXS9-DXS41-cen. An unrelated patient with the karyotype 46,X,t(X;Y) (p22;q11) retains the DXS143 locus on the derivative X chromosome but loses DXS278, suggesting that DXS278 is the more distal locus and is close to an XI/OA1 deletion boundary. If a contiguous gene deletion is responsible for the observed XI/OA1 phenotype, it localizes OA1 to the Xp22.3 region.

Arylsulfatases↗
PubMed1978

[Pathophysiology of sulfatide metabolism in metachromatic leukodystrophy].

Metachromatic leucodystrophies (MLD) comprise a small group of heredodegenerative disorders of the nervous system. Deficiency of sulfatide-sulfatase or arylsulfatase A is the common defect in all forms of MLD leading to lysosomal sulfatide storage in the nervous tissue and in the kidney. On the basis of animal experiments, experiments with cultured fibroblasts of the patients as well as ultrastructural studies in a case of prenatal MLD, the following pathomechanism is proposed: 1. Lysosomal degradation of a large portion newly synthetised sulfatide normally regulating the net synthesis and incorporation of sulfatide into myelin, causes early accumulation of sulfatide in lysosomes of myelinating cells and in neurons in the genetic deficiency of arylsulfatase A. 2. Early accumulation of sulfatide does not lead to disturbance in myelination. Demyelination occurs possibly by storage of a cytotoxic compound, psychosin sulfate, also a substrate for the missing enzyme. Prevention of MLD is possible by prenatal diagnosis of arylsulfatase A deficiency in cultured amniotic cells. Enzyme substitution of the missing arylsulfatase A is possible by exogenous uptake of the enzyme in cultured fibroblasts. Thereby the defect of sulfatide degradation can be corrected. Although principles of enzyme substitution have been demonstrated, the problems of treating patients with MLD with arylsulfatase A infusions have yet to be overcome.

Animals↗
PubMed1979

Urinary excretion of conjugated homovanillic acid, 3,4-dihydroxyphenylacetic acid, p-hydroxyphenylacetic acid, and vanillic acid by persons on their usual diet and patients with neuroblastoma.

We report quantitative data on beta-glucuronidase- and sulfatase-hydrolyzable conjugates of homovanillic acid, 3,4-dihydroxyphenylacetic acid, p-hydroxyphenylacetic acid, and vanillic acid in the urine of 20 apparently normal and healthy control persons and of three patients with neuroblastoma. We used organic solvent extraction and capillary gas chromatography. There was considerable person-to-person variation in the conjugation percentages calculated. Mean conjugated percentages of the four compounds for 16 normal healthy persons 2.5--40 years of age were, respectively, 12%, 33%, 14%, and 35%. For newborns and patients with neuroblastoma, these percentages were somewhat different. Increased amounts of vanillic acid were found in the urine of the patients with neuroblastoma, but results of a small metabolic study in rats suggest that this increase most probably is of dietary origin.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Quantitative metabolic fate of propranolol in the dog, rat, and hamster using radiotracer, high performance liquid chromatography, and gas chromatography-mass spectrometry techniques.

The complete metabolic fate of propranolol has been difficult to assess because of its complexity. The aim of this study was therefore to develop an analytical approach that would permit separation and quantitation of all major propranolol metabolites. This was accomplished in the urine of dogs, rats, and hamsters using a combination of techniques. Propranolol, 25 mg/kg, was given together with [3H]propranolol po to dogs and ip to rats and hamsters. After hydrolysis with beta-glucuronidase and sulfatase, the 0-24-hr urine was extracted with diethyl ether first at pH 9.6 to yield basic, phenolic, and neutral metabolites. This fraction contained 35 +/- 1% (mean +/- SE; N = 3) in the dog, 59 +/- 2% in the rat, and 53 +/- 5% in the hamster (based on the total radioactivity in urine). The urine was then extracted at pH 2 for acidic metabolites, yielding 32 +/- 3% in the dog, 4 +/- 1% in the rat, and 5 +/- 1% in the hamster. The pH 9.6 and pH 2 extracts were each separated into its components by HPLC. Liquid scintillation spectrometry and GC/MS allowed quantitation and identification of about 15 phase I metabolites. Major species differences existed, with glucuronidation and side chain oxidation dominating in the dog and ring oxidation in the rat and hamster. A large nonextractable fraction constituting previously unrecognized propranolol metabolites was discovered both in dogs (34 +/- 2%) and in rats (37 +/- 1%) and hamsters (40 +/- 8%). This fraction, which appeared to have a long half-life in the dog and rat, could be separated by HPLC into several distinct radioactive peaks. Preliminary attempts to identify these metabolites, which differed among species, indicated them to be highly polar and labile, some of them probably conjugates of known ring-hydroxylated metabolites.

Animals↗
PubMed1983

[Spatial distribution of thiamine pyrophosphatase and arylsulfatase activities in the area of the Golgi apparatus of the adenohypophyseal secretory cells in the white rat].

Specimens of albino rat pituitary glands were processed consecutively for demonstration of thiamine pyrophosphatase (TPPase) and aryl sulfatase (ArSase) activities. To differentiate between the structures associated with each particular enzyme studied within a single cell, either somatotroph or mammotroph, ultrathin sections were exposed for 2 minutes to 2--50% H2SO4 which removed the reaction products for TPPase rather than those for ArSase. The comparative study of pairs of micrographs of the same area taken before and after the etching with H2SO4 has shown TPPase and ArSase to reside in the Golgi apparatus and GERL system, respectively. Transitional elements have also been discovered, thus supporting the idea that GERL may be a derivative of the Golgi apparatus.

Animals↗
PubMedDate not supplied

Keratan and herparan sulfaturia: glucosamine-6-sulfate deficiency.

The pattern of excretion of urinary acid mucopolysaccharides (AMPS) has been helpful to establish the diagnosis of mucopolysaccharidoses. The importance of urine analysis for AMPS and the specific enzyme assays is exemplified in a 3 1/2 year old Caucasian male with severe mental retardation, small stature, thoracolumbar kyphosis, and dysostosis multiplex. Urine analysis for AMPS revealed excessive quantities of keratan and heparan sulfate. This mucopolysacchariduria was not associated with hepatosplenomegaly or corneal clouding. Enzymic studies on cultured skin fibroblasts indicated deficiency of N-acetylglucosamine-6-sulfate sulfatase. This enzyme deficiency is different from that responsible for Morquio's syndrome, and early recognition is essential for proper counseling.

Child, Preschool↗
PubMed1982

[Heterogeneity of formes frustes of Morquio's disease].

Two children presenting with a mild form of Morquio's syndrome are reported. Clinically, there was a characteristic brevity of the trunk and slit lamp examination showed discrete corneal opacities. On X-ray films, generalized plastyspondylia was moderate but it was associated with hypoplasia of the odontoid process. Acetabula were enlarged with coxa valga; obliquity of inferior radio-cubital extremity was associated with a sharp pattern of the proximal end of metacarpi. Epiphyseal cartilage chondrocytes also looked like those of Morquio's syndrome: large cells containing numerous vacuoles, limited by a single smooth membrane. On the other hand, no keratosulfate was found in urines and N-acetylgalactosamine-6-sulfate-sulfatase and beta-galactosidase assays in fibroblasts were normal. Thus, this mild form is different from the so-called Morquio's syndromes types A and B.

Child↗
PubMed1981

[Endocrino-pharmacological study of reproduction: Role and biosynthesis of steroid hormones in the feto-placental unit].

Although considerable information is available concerning steroidogenesis in the human fetus, the function of the different steroids formed during pregnancy and the factors regulating this delicate hormones balance are poorly understood. During human pregnancy, the placenta synthesizes large quantities of progesterone, estradiol, estrone and estriol and secretes these hormones into both the maternal and fetal circulations; progesterone from maternal lipoprotein-cholesterol, estradiol and estrone from maternal and fetal dehydroepiandrosterone sulfate (DHAS), and estriol largely from fetal 16 alpha-OH-DHAS. It has been demonstrated that preimplantation blastocysts of several animal species have the capacity to accumulate steroids to pregnenolone to progesterone, and to interconvert estrone and estradiol. Estetrol (E4), 15 alpha-hydroxy derivative of estriol is an interesting compound, since its formation is relatively unique to fetal liver function. Of special interest is that placental sulfatase deficiencies result in an extension of the gestation, and Cesarean section has to be done. This raises the question of the role of estrogens in determining the onset of labor, much as in the case of anencephaly. In general, progesterone may decline prior to an abortion, but there has not been a direct application to clinical practice. Estrogen levels during pregnancy are influenced by factors other than fetal well-being and include fetal weight, placental enzyme function, fetal adrenal function, maternal intestinal flora, maternal renal excretion and maternal liver function. Although not yet extensively utilized, such a dynamic test as the infusion of DHAS may yield useful information within a short period in otherwise complicated cases related to fetal and placental function.

Androgens↗
PubMed1983

Conjugation patterns of endogenous plasma catecholamines in human and rat. A new specific method for analysis of glucuronide-conjugated catecholamines.

Plasma free, sulfoconjugated, and glucuronoconjugated CAs were determined radioenzymatically before and after hydrolysis. CA sulfates and glucuronides were hydrolyzed by sulfatase and Ketodase, respectively. Total CA conjugates were deconjugated by acid lyophilization. On the basis of data obtained from systematical studies on these methods, the conjugation patterns of endogenous plasma CA in human and rat have been qualitatively and quantitatively identified. The results show that (1) in human plasma, sulfation is the sole conjugation mode for DA, NE, and E; (2) in rat plasma, sulfation also occurs in DA, NE, and E but the quantities of the sulfates are small, whereas glucuronidation predominates in DA and occurs exclusively in DA but not in NE and E; (3) in both species, conjugation is preferential for DA rather than NE and E. In this study, a new specific method for analysis of glucuronoconjugated CA has been developed.

Animals↗
PubMed1980

Elevated activities and properties of arylsulfatases A and B and B-variant in human lung tumors.

The activities of arylsulfatases A and B were determined in human primary and secondary tumor tissues (total, 53 cases) of various histological types. Significantly higher activities of these sulfatases were found in almost all the primary lung carcinomas as compared to their corresponding uninvolved tissues. No significant correlation was demonstrated between the enzyme activities and histological figures (stroma amounts, etc.). Lung adenocarcinoma and squamous cell carcinoma showed the presence of an additional arylsulfatase component (B1) which was not detected in normal human lung. The tumor arylsulfatase B1 had an isoelectric point (pI) of 6.7 and was clearly distinguished from arylsulfatase A (pI 4.9) and arylsulfatase B (pI 9.1 to 9.2) in normal lung and lung tumor. The tumor B1 enzyme was demonstrated to be most probably an isoenzyme of arylsulfatase B, since this unusual enzyme was indistinguishable from arylsulfatase B in terms of Ag+ inhibition; its kinetic parameters of Km for p-nitrocatechol sulfate, which was 2.9 mM with B1; optimum pH of 6.3 for B1; heat stability; and substrate specificity for three synthetic and two physiological substrates.

Adenocarcinoma↗
PubMed1995

The biochemical identification of carrier state in mothers of sporadic cases of X-linked recessive ichthyosis.

X-linked recessive ichthyosis (XLI) is an inherited inborn error of metabolism due to steroid sulfatase (STS) deficiency. The STS activity was studied in 13 families that were referred to the Genetic Department, General Hospital of Mexico City, as being affected by ichthyosis. The study was specially focused on five apparently on familial cases and their mothers, in order to identify carrier status and provide adequate genetic counseling. STS activity was determined in leucocytes using 7-[3H]-dehydroepiandrosterone sulfate as substrate. None of the XLI patients showed STS activity (pmol/mg protein/h), four mothers had an activity compatible with a carrier state (0.19 +/- 0.02 vs 0.66 +/- 0.14 males or 0.90 +/- 0.30 females pmol/mg protein/h, p < 0.001) and only one mother showed a normal pattern, indicating that her son had a de novo mutation. It is important to determine the STS activity in the propositus mother of apparently non familial cases of XLI to identify the carrier state and provide and accurate genetic counseling, as most of these seem to correspond to inherited cases.

Adolescent↗
PubMed1994

Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): six unique arylsulfatase B gene alleles causing variable disease phenotypes.

Mucopolysaccharidosis type VI, or Maroteaux-Lamy syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase B (ASB), also known as N-acetylgalactosamine-4-sulfatase. Multiple clinical phenotypes of this autosomal recessively inherited disease have been described. Recent isolation and characterization of the human ASB gene facilitated the analysis of molecular defects underlying the different phenotypes. Conditions for PCR amplification of the entire open reading frame from genomic DNA and for subsequent direct automated DNA sequencing of the resulting DNA fragments were established. Besides two polymorphisms described elsewhere that cause methionine-for-valine substitutions in the arylsulfatase B gene, six new mutations in six patients were detected: four point mutations resulting in amino acid substitutions, a 1-bp deletion, and a 1-bp insertion. The point mutations were two G-to-A and two T-to-C transitions. The G-to-A transitions cause an arginine-for-glycine substitution at residue 144 in a homoallelic patient with a severe disease phenotype and a tyrosine-for-cysteine substitution at residue 521 in a potentially heteroallelic patient with the severe form of the disease. The T-to-C transitions cause an arginine-for-cysteine substitution at amino acid residue 192 in a homoallelic patient with mild symptoms and a proline-for-leucine substitution at amino acid 321 in a homoallelic patient with the intermediate form. The insertion between nucleotides T1284 and G1285 resulted in a loss of the 100 C-terminal amino acids of the wild-type protein and in the deletion of nucleotide C1577 in a 39-amino-acid C-terminal extension of the ASB polypeptide. Both mutations were detected in homoallelic patients with the severe form of the disease. Expression of mutant cDNAs encoding the four amino acid substitutions and the deletion resulted in severe reduction of both ASB protein levels and arylsulfatase enzyme activity in comparison with a wild-type control. The six mutations described in the present study were unique among 25 unrelated mucopolysaccharidosis VI patients, suggesting a broad molecular heterogeneity of the Maroteaux-Lamy syndrome.

Alleles↗
PubMed1993

[Screening of principal enzymes involved in the metabolism of anticancer drugs in human and murine colonic tumors].

Since drug-metabolizing enzymes may influence the toxic response of tissues or organs to drugs, we studied their expression in human and colon tumor tissues, in an attempt to find new targets for chemotherapy and also to explain the intrinsic drug-insensitivity of most colon tumors to anticancer drugs. In the present work, we compared human colorectal tumors and peritumoral tissues to a mouse colorectal tumor (Co38) and normal murine colon with regard to their main drug-metabolizing enzyme systems. We investigated cytochromes P-450 (1A1/1A2, 2B1/B2, 2C, 2E1, 3A) and epoxide hydrolase (EH) by immunoblotting. Total glutathione (GSH) and the activities of the following enzymes: total GST, selenium-independent glutathione peroxidase (GPX), 1,2-dichloro-4-nitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), UDP-glucuronosyltransferase 1 (UDPGT), beta-glucuronidase (beta G), sulfotransferase (ST) and sulfatase (S) were investigated by fluorometric and spectrophotometric assays. Results obtained by immunoblotting showed that mouse colon tumor Co38 did not express any of the probed cytochromes P-450, whereas human tumors showed the presence of cytochrome P-450 3A. EH was not expressed in either mouse colon tumor Co38 or normal mouse colon, whereas it was expressed in human peritumoral and tumoral colon tissues at similar levels. GPX and EA-GST were detected in all tumoral and non tumoral tissues of both species. DCNB-GST was expressed in all murine tissues investigated, but was not found in human tissues. For human peritumoral and tumoral colorectal tissues there was no significant difference between GST isoenzymes levels, whereas mouse colon tumor Co38 had a lower expression of DCNB-GST and EA-GST compared to normal mouse colon. No significant difference was observed between human tumors and peritumoral tissues for total GST, UDPGT1, beta G, ST and S activities. For murine colon tissues, the conjugation pathways (total GST, UDPGT1 and ST) were lower in Co38, whereas the opposite was observed for the hydrolytic enzymes (beta G and S). In conclusion, despite similarities between human and murine colon tumors, mouse colon tumor Co38 appears different from human colon tumors for many drug-metabolizing enzyme systems. These interspecies differences may have implications with regard to drug screening methodologies and preclinical evaluation of candidate anticancer drugs useful in the chemotherapy of human colorectal tumors.

Aged↗