Gene/Protein Disease Symptom Drug Enzyme Compound
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Recent reports have thrown doubt on the role of measurements of plasma 5 alpha-androstane-3 alpha,17 beta-diol glucuronide (3 alpha-diolG) as a marker of peripheral androgen metabolism in women with polycystic ovarian syndrome and idiopathic hirsutism. It has been suggested that a plasma profile of C19 steroid glucuronides may be more informative. While preliminary data indicates that both 3 alpha-diolG and androsterone G (ADTG) may arise from adrenal steroid precursors, there have been no reports of C19 steroid glucuronides in women with non-classical, or late-onset congenital adrenal hyperplasia (NC-CAH), who constitute a significant proportion of the hirsute female population. We therefore measured plasma levels of 3 alpha-diolG, ADTG and dihydrotestosterone G (DHTG) before and following a standard Cortrosyn test in 15 symptomatic and 3 asymptomatic NC-CAH patients, 5 heterozygote carriers for 21-hydroxylase deficiency (NCHETS) and 18 normal women. The effects of chronic glucocorticoid (GCR) therapy (greater than 3 months) on the C19 steroid glucuronide profile in the symptomatic patients was also investigated. Baseline plasma levels of all 3 glucuronides were significantly (P less than 0.001) higher in symptomatic patients compared with either normals or NCHETS. However, the order of discrimination was ADTG greater than 3 alpha-diolG greater than DHTG. There were no significant differences between steroid glucuronide levels for NCHET and normal women and the C19 steroid glucuronide concentrations for the asymptomatic NC-CAH patients were greater than 2 SD above the normal means. Moderate clinical improvement was observed in all patients receiving oral GCR therapy and was accompanied by approx. 80% suppression of the plasma levels of all 3 C19 steroid glucuronides. This contrasts with a mean suppression of androstenedione of only 50%. However, plasma levels of the C19 steroid glucuronides were not significantly increased in response to a short ACTH stimulation test. This may be explained by the fact that the androgen glucuronides are thought to be peripherally formed metabolites derived from unconjugated glandular secreted androgen precursors and thus their synthesis at 60 min following adrenal stimulation may lag substantially behind that of their respective precursors. There were significant linear correlations between the levels of all 3 glucuronides, but neither correlated with Ferriman-Gallway scores, body mass index or 17-hydroxyprogesterone levels.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1992 Apr
PMID:Plasma levels of C19 steroid glucuronides in pre-menopausal women with non-classical congenital adrenal hyperplasia. 131 40

Female Swiss mice were treated for 24 weeks, with 3-hydroxy-4-pyrone (Py) added to their powdered diet at 0.5% (wt/wt), and the effects of this agent on the liver were examined. Serum transaminases (especially GPT) rose continuously, while the GOT/GPT ratio remained at approximately 1.0 throughout the study period. The characteristic changes found from 8 weeks onward were piecemeal necrosis and bridging necrosis of the hepatocytes with dense lymphocytic infiltration. Proliferation of collagen fibers in the portal tracts and formation of narrow fibrous septa dividing the lobules into pseudolobules were also noted from 12 weeks onward. A large number of the infiltrating lymphocytes were identified as T cells by immunohistochemical and electron microscopic studies. These lymphocytes often surrounded or were closely attached to degenerating hepatocytes. Focal apoptosis and necrosis accompanied by a granulomatous reaction of the centrilobular hepatocytes were noted as early changes in the liver. Our findings indicate that the hepatic changes produced in mice by long-term Py administration have characteristics in common with those of human chronic active hepatitis. Immunological cytotoxic mechanisms, especially T cell-mediated ones, appear to play an essential role in the development of hepatic lesions in this murine model of chronic active hepatitis.
Exp Mol Pathol 1992 Oct
PMID:Pathology of chemically induced chronic active hepatitis in mice. 142 59

To clarify whether glycyrrhizin, the aqueous extract of licorice root and a drug for treatment of chronic active hepatitis, prevents the development of hepatic injury induced by carbon tetrachloride, allyl formate, and endotoxin, the present study was undertaken in rats. The treatment with glycyrrhizin 20 hr before carbon tetrachloride administration protected the development of the pericentral hepatocellular necrosis. Glycyrrhizin treatment 2 hr prior to the administration of allyl formate also inhibited the development of the periportal hepatocellular necrosis. However, glycyrrhizin did not protect the development of endotoxin-induced focal and random hepatocellular necrosis. These experimental results suggest that glycyrrhizin has no protective effect on hepatic injury following sinusoidal circulatory disturbance as seen in the case of endotoxin and that glycyrrhizin can protect against hepatotoxicity induced by the direct action on the hepatocytes due to hepatotoxins, such as carbon tetrachloride and allyl formate.
Exp Mol Pathol 1989 Aug
PMID:Prevention of hepatotoxic responses to chemicals by glycyrrhizin in rats. 276 17

The development of a non-competitive, solid-phase radioimmunoassay for quantitating anti-actin antibody is described. Anti-actin antibody was captured on BSA-coated microspheres of polystyrene to which a synthetic peptide representing the fifteen amino acid N-terminus of human beta-actin was covalently attached. A rabbit antiserum against the actin peptide fragment was used as reference serum for the assay. Serums of 23 out of 28 (82%) patients with chronic active hepatitis, shown to have anti-actin antibodies (range 2-140 micrograms ml-1) by immunofluorescence and immunoblot assays, were used to validate the radioimmunoassay. Only 7 out of 130 (5%) control subjects exhibited anti-actin antibody serum concentrations above 14 micrograms ml-1 (range 2-20 micrograms ml-1), the 95% confidence interval. Anti-actin antibody serum concentrations were determined to be elevated in 28 out of 47 (60%) patients with juvenile rheumatoid arthritis (range 5-89 micrograms ml-1), 43 out of 64 (67%) patients with human immunodeficiency virus infection and AIDS (range 3-80 micrograms ml-1), and 17 out of 23 (74%) infants with Kawasaki Syndrome (range 7-138 micrograms ml-1). All of the differences observed between patient groups, either singly or collectively, and the control group are highly significant (P less than 0.001) as judged by chi-square analysis. Since all of these disease states contain elements of viral infection and autoimmune disease, it is possible that viral infection in these diseases triggers the production of anti-actin antibody, possibly by means of molecular mimicry in response to viral oncogenes or to abnormal expression of actin in host tissue. This radioimmunoassay for anti-actin antibodies may prove to be a useful tool for the detection and monitoring of certain forms of autoimmune disease.
Mol Cell Probes 1988 Dec
PMID:Radioimmunoassay for anti-actin antibody: application in viral and autoimmune diseases. 307 13

The behavior of hepatitis C virus (HCV) infection with regards to type and number of HCV genotypes (tested with genotype-specific nested polymerase chain reaction) was evaluated in 60 patients with anti-HCV-positive chronic active hepatitis without cirrhosis [17 untreated and 43 subjects undergoing single or repeat courses of interferon (IFN) therapy] during a mean follow-up period of 76 +/- 18 months. In untreated patients (2 genotype I, 6 genotype II, 9 mixed infections) 4 out of 9 mixed infections selected for genotype II at the end of follow-up. Of the 43 treated patients 10 were long-term responders with histological remission, 6 were short-term responders, and 22 did not respond. Fifteen of the latter patients received another course of IFN therapy, and only 3 patients responded. Eight of the 10 responders had infection with a single genotype (4 gt I, 3 gt II, 3 gt III). After IFN therapy, all but 2 patients cleared the HCV infection. The responders to the second IFN course (1 gt I, 1 gt II, 1 gt III) remained viremic. Of the short-term responders, 2/6 patients had genotype II and 4 had a mixed infection (3 gt II +/- I and 1 gt II +/- III); gt III became prevalent in the latter in all but one patient. Of the nonresponders 18/24 had more than one genotype, 5 were genotype II at baseline and one had genotype I. At the end of the follow-up period 15/18 with mixed infection had selected for gt II (P < 0.01 vs. untreated patient).(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Med (Berl) 1995 May
PMID:Selection of more pathogenic hepatitis C virus genotype II during long-term follow-up of interferon-treated patients. 754 26

Biopsy specimens (n = 61) from patients with chronic active hepatitis B and progressive fibrosis (n = 61) were studied immunohistochemically to obtain information about the histogenesis of neoductules. All the biopsies contained clusters of oval-shaped cells often arranged in the form of neoductular aggregates. These expressed cytokeratins 7 and 19 which in the normal liver are found only in bile duct and ductular epithelium but not in hepatocytes. Using monoclonal and polyclonal antibodies both hepatocytes and these oval neoductular cells were found to express HBs- and HBc-antigen in 15% and 20% of the biopsies, respectively. Taking into consideration the strong hepatocytotropism of the hepatitis B virus, the expression of HBV-antigens in neoductular cells suggest their development from HBV-infected hepatocytes. Using proliferating cell nuclear antigen (PCNA) as a marker of cell proliferation positive staining was detected only in hepatocytes but not in neoductular cells. Taken together findings further support the concept of hepatoductular metaplasia in the histogenesis of so-called "proliferating" ductules. In general the data show that hepatitis B virus infection does not prevent hepatocytes from undergoing ductular metaplasia.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Expression of HBs- and HBc-antigen in neoductular epithelium in chronic active hepatitis B. A further support for hepato-ductular metaplasia. 809 73

Studies in human beings, animals, and cell systems show that the rate-limiting step in steroidogenesis is the conversion of cholesterol to pregnenolone. In the adrenals and gonads, this step is subject to both acute and chronic regulation. Chronic regulation is primarily, but not exclusively at the level of gene transcription, leading to the production of more steroidogenic machinery and thus increasing the cellular capacity for steroidogenesis. Chronic regulation can be inhibited by inhibiting protein synthesis with cycloheximide, but this response varies among various cell types and species. Although the P450scc enzyme system that converts cholesterol to pregnenolone is inherently very slow, the principal site of acute regulation is at the delivery of free cholesterol to mitochondria, rather than at the delivery of reducing equivalents to P450scc. Even when the Vmax of the P450scc system is increased 6-fold by genetic engineering, delivery of cholesterol to the enzyme remains rate-limiting. Targeting of a genetically engineered fusion of the P450scc system to either mitochondria or to the endoplasmic reticulum of non-steroidogenic cells demonstrates that the mitochondrial environment is absolutely required for the conversion of cholesterol to pregnenolone, and that this absolute requirement is not based on either the nature of the available electron donors for P450scc or the availability of substrate. Various factors have been proposed as the essential mediator for the transport of cholesterol into mitochondria to initiate steroidogenesis. A recently identified protein termed Steroidogenic Acute Regulatory protein (StAR) has the necessary properties of enhancing steroidogenesis, rapid cAMP inducibility and rapid cycloheximide sensitivity that characterize the long-sought acute regulator of steroidogenesis. StAR is expressed in steroidogenic tissues exhibiting an acute response but not in steroidogenesis. StAR is expressed in steroidogenic tissues exhibiting an acute response but not in steroidogenic tissues (placenta, brain) that do not exhibit this response. Mutations in StAR are now shown to cause Congenital Lipoid Adrenal Hyperplasia, the last unsolved form of CAH. The actions of StAR can be circumvented by the use of hydroxycholesterols that can freely diffuse into mitochondria, proving that StAR functions as an acute regulator of cholesterol access to mitochondria.
J Steroid Biochem Mol Biol 1995 Dec
PMID:Mitochondrial specificity of the early steps in steroidogenesis. 854 88

Congenial lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH. Affected individuals can make no adrenal or gonadal steroids. All affected individuals are phenotypic females irrespective of gonadal sex, and frequently die in infancy if mineralocorticoid and glucocorticoid replacements are not instituted. Recent data implicate the steroidogenic acute regulatory (StAR) protein in this disorder. We now describe a 46,XY patient of Vietnamese ancestry with lipoid CAH who had a somewhat milder form of the disease. Diagnosis was at 10 weeks of age, and low levels of plasma progesterone, corticosterone, 180H-corticosterone and androstenedione were detectable. Testicular RNA for StAR was reverse transcribed, amplified, cloned and sequenced, revealing a 185 bp deletion corresponding to all of exon 5. The corresponding mRNA did not encode active protein in transfected cells. Cloned genomic DNA from the patient revealed only a T-->A transversion in intron 4,11 bp from the splice acceptor site of exon 5. This transversion destroys an NcoI site; digestion of PCR-amplified genomic DNA from the patient and both parents confirmed that the patient was homozygous and the parents were heterozygous. Expression vectors for StAR minigenes were constructed containing all StAR exons plus introns 4, 5 and 6 either with or without the T-->A mutation in intron 4. RNase protection assays showed that expression of the vector with normal intron 4 yielded correctly spliced StAR mRNA in transfected COS-1 cells, while most, but not all StAR mRNA from the vector with the T-->A transversion in intron 4 was abnormally spliced. RNase protection of the patient's testicular RNA confirmed that most, but not all StAR mRNA was similarly spliced abnormally. Splicing errors appear to be a rare cause of genetic diseases, but subtle intronic mutations may be missed when genomic DNA is the only material available for study. The low level of normal StAR mRNA produced may account for the later clinical presentation and low levels of steroid hormones detected in this patient.
Hum Mol Genet 1995 Dec
PMID:T-->A transversion 11 bp from a splice acceptor site in the human gene for steroidogenic acute regulatory protein causes congenital lipoid adrenal hyperplasia. 863 2

Erythrocyte membrane Na+,K+: Ca2+ ATP ase activities, cholesterol (CH) phospholipid (PL) composition and erythrocyte glutathione (GSH) contents were determined in controls, in patients with chronic active hepatitis and liver cirrhosis. NA+,K+ ATP ase activities were significantly (P < 0.0001) less in patients with chronic active hepatitis and liver cirrhosis (n = 8, 0.102 +/- 0.02 mumol P/mg protein/hour; n = 8, 0.081 +/- 0.02 mumol P/mg protein/hour) than in controls (n = 10, 0.219 +/- 0.05). Histopathological analysis of liver sections obtained from patients with chronic active hepatitis (n = 3) and liver cirrhosis (n = 2) correlated well with erythrocyte biochemical findings. There was a significant negative correlation between Na+,K+ ATP ase activity and portal fibrosis (P < 0.05, r = -8680). However, further experiments performed on larger study populations are needed to better elucidate this correlation. Therefore, NA+K+ ATP ase activity measurement can be reliable assessment of liver fibrosis.
Biochem Mol Biol Int 1996 Nov
PMID:Erythrocyte membrane Na+,K+ ATP ase activity can be a marker of liver histopathology. 895 35

We have isolated a 29,000-Da carbonic anhydrase (CA) protein from the zebrafish, Danio rerio, sequenced two peptide fragments, and tentatively identified it as a high-activity CA by inhibition kinetics. We have also characterized a 1,537-bp message whose deduced sequence of 260 amino acids matches that of the isolated protein. This CA is clearly an alpha-CA based on the similarity of its sequence to that of other members of the alpha-CA gene family. A phylogenetic analysis suggested CAH-Z diverged after the branching of the CA-V and CA-VII genes and prior to the duplications that generated the CA-I, CA-II, and CA-III genes of amniotes. This marks the first characterization of the mRNA and its protein product from the CA gene of a teleost.
J Mol Evol 1997 Apr
PMID:Isolation and characterization of a carbonic anhydrase homologue from the zebrafish (Danio rerio). 908 83


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