Biomedical subjects

J A Cuthbert

Publications and source records attributed to J A Cuthbert.

At least 19 recordsLinked to original sources

PubMed1997

Acute sporadic non-A, non-B, non-C, non-D, non-D, non-E hepatitis.

Patients presenting with clinical and laboratory features consistent with a diagnosis of acute non-A, non-B hepatitis were evaluated for evidence of hepatitis C or hepatitis E infection and for evidence of severe or prolonged disease. Antibody to hepatitis C virus (anti-HCV) was detected in 75 of 108 (69%) patients, antibody to hepatitis E virus (anti-HEV) in three patients (3%), and neither antibody in 31 (29%) patients. One patient had both anti-HCV and anti-HEV. HCV RNA was not detected in sera from any of 20 patients with seronegative (non-ABCDE) hepatitis, but in all 10 patients with anti-HCV who were tested by polymerase chain reaction (PCR). Compared with patients with acute hepatitis C, those with non-ABCDE hepatitis had a lower incidence of parenteral risk factors (6% vs. 70%; P < .001), higher peak serum bilirubin levels (45% vs. 5% with peak levels > 15 mg/dL; P < .001), more prolonged jaundice (25% vs. 0% with peak bilirubin >5 weeks after onset; P < .01), more severe prothrombin time abnormalities (26% vs. 0% with >3 second prolongation; P < .001), more severe hypoalbuminemia (39% vs. 9% with albumin <3 g/dL; P < .01), and more frequent major clinical complications (13% vs. 0% with encephalopathy; P < .01; 10% vs. 0% with death or transplant; P = .024). Patients with acute non-ABCDE hepatitis were less likely to develop chronic hepatitis than those with acute hepatitis C (23% vs. 68%; P < .05). Thus, patients with acute non-ABCDE hepatitis are epidemiologically distinct from those with acute hepatitis C and have a significantly more severe acute illness.

Adolescent↗

PubMed1996

Feedback regulation of hepatic 7alpha-hydroxylase expression by bile salts in the hamster.

Hepatic 7alpha-hydroxylase activity appears to be regulated at the transcriptional level by the quantity of bile salts fluxing through the enterohepatic circulation. Whether bile salts directly suppress 7alpha-hydroxylase expression at the level of the hepatocyte or do so indirectly by promoting the release or absorption of an intestinal factor has not been resolved. We have investigated the ability of primary bile salts to suppress hepatic 7alpha-hydroxylase expression in bile-diverted hamsters. Biliary diversion was accompanied by derepression of both hepatic 7alpha-hydroxylase activity (4-5-fold) and bile salt secretion (approximately 3-fold). Derepression of hepatic 7alpha-hydroxylase expression could be prevented by several interventions that increase the availability of bile salts within the hepatocyte including 1) overexpression of an exogenous 7alpha-hydroxylase gene by adenovirus-mediated gene transfer, 2) obstruction of the common bile duct, and 3) intravenous infusions of taurocholate. In contrast, none of these interventions prevented derepression of hepatic cholesterol synthesis or significantly down-regulated hepatic low density lipoprotein receptor expression over the relatively short time course (24 h) of these studies. Together, these data indicate that primary bile salts contribute to the regulation of bile salt synthesis through feedback repression of 7alpha-hydroxylase expression at the level of the hepatocyte.

Adenoviridae↗

PubMed1996

Steroid therapy of chronic hepatitis: characteristics associated with response in anti-hepatitis C virus-positive and -negative patients.

OBJECTIVES: The goals of this study were to examine responses to corticosteroid-containing therapy in non-B chronic hepatitis patients with different anti-hepatitis C virus (HCV), autoantibody, and biochemical test results and to determine what factors correlate with response. METHODS: Patients with a prior or current history of steroid therapy for putative autoimmune or chronic non-A, non-B hepatitis were assessed. Responses during the first 6 months of therapy were categorized as "complete" (normal aminotransferases for > or = 1 month), "partial" ( > 50% reduction), or "no response." RESULTS: Sufficient data available to permit evaluation in 32 patients. Complete responses were noted in 17, partial responses in 12, and no response in three subjects. By multivariate analysis, only absence of anti-HCV and presence of cirrhosis were independent predictors of response. Nonresponders were found to have lower scores in a proposed autoimmune hepatitis scoring system, but scores of complete and partial responders were not significantly different. Despite a lower likelihood of a complete response, 80% (12/15) of patients with multiantigen positive anti-HCV tests had either partial or complete initial responses to corticosteroid-containing therapy, and, in nine patients, aminotransferases fell to < 2 times the upper limit of normal. All 15 anti-HCV-negative patients, but only three of 15 anti-HCV-positive patients, entered complete responses that were sustained (aminotransferases < twofold abnormal) on regimens containing < 20 mg/day or prednisolone or prednisone. CONCLUSIONS: Although anti-HCV-positive patients frequently exhibit partial initial responses to immunosuppressive therapy, the absence of specific anti-HCV antibodies was better as a predictor of completeness of response than assessment of autoantibodies or degree of biochemical abnormalities.

Adrenal Cortex Hormones↗

PubMed1995

Suppression of the proliferation of Ras-transformed cells by fluoromevalonate, an inhibitor of mevalonate metabolism.

Mevalonate is the precursor of a number of different products potentially required for the growth of cells, including the prenylated oncoprotein Ras. To determine whether inhibition of mevalonate metabolism would selectively block proliferation of Ras-transformed cells, 6-fluoromevalonate (Fmev), an inhibitor of diphosphomevalonate decarboxylase, was used to block the synthesis of prenyl-derived lipids and prenylated proteins in interleukin-3 (IL-3)-dependent FDC-P1 cells (control FDC-P1 cells) and FDC-P1 cells transformed with oncogenic Ras (RasDC cells) that proliferated in the absence of IL-3. Fmev completely inhibited synthesis of prenyl-derived lipids and prenylated proteins and blocked proliferation of FDC-P1 and RasDC cells. Restoration of the proliferation of Fmev-blocked FDC-P1 cells required both an exogenous source of cholesterol and prevention of the accumulation of mevalonate and the mevalonate phosphates with lovastatin. In contrast, ongoing IL-3-independent proliferation of Fmev-blocked RasDC cells was not completely restored by providing exogenous cholesterol and preventing the accumulation of inhibitory mevalonate product(s). However, these cells proliferated when cultures were supplemented with IL-3 together with exogenous cholesterol and lovastatin, implying that Fmev had prevented Ras-dependent, IL-3-independent growth. Fmev markedly diminished total cellular Ras in RasDC cells. In contrast, lovastatin depleted membrane-associated Ras and increased cytosolic Ras but did not diminish total cellular Ras. These data indicate that Fmev depletes total cellular Ras and specifically inhibits the autonomous growth of Ras-transformed cells.

Animals↗

PubMed1995

Regulation of hepatic 7 alpha-hydroxylase expression and response to dietary cholesterol in the rat and hamster.

Although dietary cholesterol raises plasma total and low density lipoprotein (LDL) cholesterol concentrations, the response to a given intake of cholesterol varies enormously among different species and even among individuals of the same species. The mechanisms responsible for differing sensitivity to dietary cholesterol were examined by comparing the rat, which is able to adapt to large fluctuations in sterol intake or loss with little change in plasma LDL levels, with the hamster, where changes in sterol balance strongly influence plasma LDL concentrations. When fed the same cholesterol-free diet, hepatic 7 alpha-hydroxylase activity was 16-fold higher in the rat than in the hamster. As a consequence, rates of hepatic cholesterol synthesis were 20-fold higher in the rat than in the hamster. In both species, hepatic cholesterol synthesis was suppressed > 90% in response to increasing loads of dietary cholesterol. However, the quantitative importance of this adaptive mechanism was much greater in the rat since the absolute reduction in hepatic cholesterol synthesis in the rat (2,110 nmol/h/g) was much larger than in the hamster (103 nmol/h/g). In the rat, the high basal level of 7 alpha-hydroxylase expression was further induced by substrate (cholesterol) allowing these animals to convert excess dietary cholesterol to bile acids efficiently. In contrast, the low basal level of enzyme expression in the hamster was not induced by dietary cholesterol. Thus, the low basal rates of bile acid and cholesterol synthesis coupled with a lack of 7 alpha-hydroxylase induction by cholesterol render the hamster much more sensitive than the rat to the cholesterolemic effects of dietary cholesterol.

Animals↗

PubMed1995

Adenovirus-mediated transfer of a gene encoding cholesterol 7 alpha-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol.

Clinical interventions that accelerate conversion of cholesterol to bile acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations. The initial and rate-limiting step in the bile acid biosynthetic pathway is catalyzed by hepatic cholesterol 7 alpha-hydroxylase. To examine the effects of transient primary overexpression of this enzyme on sterol metabolism and lipoprotein transport, we constructed a recombinant adenovirus in which a cDNA encoding rat 7 alpha-hydroxylase is expressed from the human cytomegalovirus immediate-early promoter (AdCMV7 alpha). Syrian hamsters administered AdCMV7 alpha intravenously accumulated transgene-specific mRNA in the liver and demonstrated a dose-dependent increase in hepatic microsomal 7 alpha-hydroxylase activity. The increased conversion of cholesterol to bile acids resulted in a compensatory increase in hepatic cholesterol synthesis. In addition, overexpression of 7 alpha-hydroxylase reduced the rate of LDL cholesterol entry into the plasma space and, in animals maintained on a Western-type diet, restored hepatic LDL receptor expression. As a consequence, plasma LDL concentrations fell by approximately 60% in animals maintained on control diet and by approximately 75% in animals consuming a Western-type diet. Plasma high density lipoprotein cholesterol levels were reduced to a lesser degree. These results demonstrate that transient upregulation of bile acid synthesis by direct transfer of a 7 alpha-hydroxylase gene favorably alters circulating lipoprotein profiles and suggest one potential molecular target for genetic strategies aimed at reducing cardiovascular risk.

Adenoviridae↗

PubMed1995

Skin irritation testing in man for hazard assessment--evaluation of four patch systems.

1. The limitations of the Draize rabbit skin irritation test for hazard evaluation for man are widely documented. Nevertheless it remains the prescribed method for determining acute skin irritations hazard. 2. While the use of human testing for risk assessment of irritants is well established, the use of predictive testing in man for hazard identification has not been explored widely, and this is the object of the research programme. 3. The experiment described in this report evaluates the sensitivity of four patch testing systems (Finn chamber, Hill Top patch, Van der Bend chamber, and Webril patch) using a total of six irritant substances. 4. Following preliminary range-finding experiments, test materials were applied to the upper outer arm for up to 4 h. Assessments were performed immediately after patch removal and at 1, 24, 48, and 72 h. 5. Webril and Hill Top patches generated the greatest levels of response, although responses with Finn and Van der Bend were observed. Hill Top patches are recommended for future development work. 6. The use of very small preliminary panels to predict the effects in larger panels using different volunteers was only of limited value as each volunteer was found to have different irritant thresholds.

Acetates↗

PubMed1995

Wilson's disease: a new gene and an animal model for an old disease.

Wilson's disease is an autosomal recessive, inherited disorder of copper metabolism. In normal individuals, copper homeostasis is controlled by the balance between intestinal absorption of dietary copper and hepatic excretion of excess copper in bile. In Wilson's disease, hepatic copper is neither excreted in bile nor incorporated into ceruloplasmin and copper accumulates to toxic levels. The Wilson's disease gene (WND) encodes a putative copper-transporting protein that is expressed almost exclusively in the liver. The predicted structure of the protein product is that of a P-type ATPase with striking homology to bacterial copper transporters and the gene product of another inherited disorder of copper metabolism, Menkes' disease. A rat model of Wilson's disease has recently been identified. The Long-Evans Cinnamon (LEC) rat manifests elevated hepatic copper, defective incorporation of copper into ceruloplasmin, and reduced biliary excretion of copper. The rat homologue of the WND is abnormal in LEC rats. Clinical manifestations of Wilson's disease arise directly from copper-induced damage to hepatocytes (hepatic presentation) or indirectly after the release of copper from the liver with subsequent damage to the brain (neuropsychiatric presentation) and other organs. Genetic heterogeneity (different mutations in a single gene) may account for some of the variability in Wilsonian presentations. The diagnosis of Wilson's disease depends on the demonstration of disordered copper metabolism, manifested as elevated urinary and hepatic copper and low ceruloplasmin levels. However, none of the abnormal findings in Wilson's disease is pathognomonic. Genetic diagnosis, in the absence of family studies, is likely to be difficult since many different mutations result in the disease. Management of Wilson's disease involves decreasing excess levels of copper accumulated in the liver, brain, and other organs. Copper chelation therapy, to increase urinary excretion of copper, is the mainstay of treatment. In addition, oral zinc therapy may be useful at decreasing absorption of dietary copper and rendering tissue copper nontoxic, by increasing the formation of complexes with copper-binding proteins. Liver transplantation can be necessary for individuals with acute hepatic failure or complications of cirrhosis. Gene therapy may evolve in the future; however, medical management is effective in most patients.

Amino Acid Sequence↗

PubMed1995

Regulatory effects of n-3 polyunsaturated fatty acids on hepatic LDL uptake in the hamster and rat.

These studies were undertaken to investigate the mechanisms involved in the regulation of hepatic low density lipoprotein (LDL) transport by n-3 fatty acids in the hamster and rat. Animals were fed n-3 or n-6 fatty acids with a cholesterol-free, very-low-fat semisynthetic diet, or with a diet enriched with cholesterol and saturated fat. Although the enrichment of liver lipids with dietary n-3 fatty acids was similar in hamsters and rats, the effect of n-3 fatty acids on hepatic LDL transport differed in the two species. In the hamster, n-3 fatty acids had no effect on hepatic receptor-dependent LDL uptake in animals fed a cholesterol-free, very-low-fat diet and suppressed receptor-dependent transport in animals fed a diet enriched with cholesterol and saturated triglyceride. In hamsters fed n-3 fatty acids, changes in receptor-dependent LDL transport were accompanied by parallel changes in LDL receptor mRNA, indicating regulation of the receptor at the pretranslational level. In the rat, on the other hand, dietary n-3 fatty acids enhanced hepatic receptor-dependent LDL uptake by nearly twofold regardless of the background diet; however, hepatic LDL receptor protein and mRNA were unchanged. Dietary n-3 fatty acids did not enhance hepatic chylomicron remnant clearance in the rat. These studies confirm marked species differences in response to n-3 fatty acids and suggest that n-3 fatty acids accelerate hepatic receptor-dependent LDL transport in the rat by altering the distribution or recycling of LDL receptors or via effects on a different receptor pathway.

Animals↗

PubMed1994

Hepatitis C: progress and problems.

The hepatitis C virus (HCV), a single-stranded RNA virus, is the major cause of posttransfusion hepatitis. HCV isolates differ in nucleotide and amino acid sequences. Nucleotide changes are concentrated in hypervariable regions and may be related to immune selection. In most immunocompetent persons, HCV infection is diagnosed serologically, using antigens from conserved regions. Amplification of RNA may be necessary to detect infection in immunosuppressed patients. Transmission by known parenteral routes is frequent; other means of spread are less common and may represent inapparent, percutaneous dissemination. Infection can lead to classical acute hepatitis, but most infected persons have no history of acute disease. Once infected, most individuals apparently remain carriers of the virus, with varying degrees of hepatocyte damage and fibrosis ensuing. Chronic hepatitis may lead to cirrhosis and hepatocellular carcinoma. However, disease progression varies widely, from less than 2 years to cirrhosis in some patients to more than 30 years with only chronic hepatitis in others. Determinants important in deciding outcome are unknown. Alpha interferon, which results in sustained remission in selected patients, is the only available therapy. Long-term benefits from such therapy have not been demonstrated. Prevention of HCV infection by vaccination is likely to be challenging if ongoing viral mutation results in escape from neutralization and clearance.

Acute Disease↗

PubMed1994

Regulation of hepatic 7 alpha-hydroxylase expression by dietary psyllium in the hamster.

Soluble fiber consistently lowers plasma total and low density lipoprotein (LDL)-cholesterol concentrations in humans and various animal models including the hamster; however, the mechanism of this effect remains incompletely defined. We performed studies to determine the activity of dietary psyllium on hepatic 7 alpha-hydroxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and LDL receptor expression in the hamster. In animals fed a cholesterol-free semisynthetic diet containing 7.5% cellulose (avicel) as a fiber source, substitution of psyllium for avicel increased hepatic 7 alpha-hydroxylase activity and mRNA levels by 3-4-fold. Comparable effects on 7 alpha-hydroxylase expression were observed with 1% cholestyramine. Psyllium also increased hepatic 7 alpha-hydroxylase activity and mRNA in animals fed a diet enriched with cholesterol and triglyceride. Activation of 7 alpha-hydroxylase was associated with an increase in hepatic cholesterol synthesis that was apparently not fully compensatory since the cholesterol content of the liver declined. Although dietary psyllium did not increase hepatic LDL receptor expression in animals fed the cholesterol-free, very-low-fat diet, it did increase (or at least restore) receptor expression that had been downregulated by dietary cholesterol and triglyceride. Thus, 7.5% dietary psyllium produced effects on hepatic 7 alpha-hydroxylase and LDL metabolism that were similar to those of 1% cholestyramine. Induction of hepatic 7 alpha-hydroxylase activity by dietary psyllium may account, in large part, for the hypocholesterolemic effect of this soluble fiber.

Animals↗

PubMed1994

Non-sterol regulation of low density lipoprotein receptor gene expression in T cells.

Non-sterol regulation of low density lipoprotein (LDL) receptor gene expression was examined in a mitogen-responsive human T cell line. Stimulation of the leukemic T cell line Jurkat with the phorbol ester phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin rapidly and transiently increased LDL receptor mRNA levels. Inhibition of protein synthesis with cycloheximide (CHX) or puromycin resulted in superinduction of LDL receptor mRNA levels by mitogenic stimulation. The increase in LDL receptor mRNA levels resulted from increased gene transcription rather than stabilization of mRNA half-life. Thus, similar results were obtained when reporter gene expression was assessed in Jurkat cells transfected with LDL receptor promoter constructs and mRNA half-life was not significantly altered by the stimuli. Neither mitogenic induction nor superinduction of LDL receptor mRNA levels in Jurkat cells was prevented by sterol downregulation of LDL receptor gene expression. The protein synthesis inhibitors CHX and anisomycin, but not puromycin, also directly stimulated LDL receptor mRNA levels, suggesting that these compounds could provide a signal required for LDL receptor gene transcription. Taken together, these data indicate that various non-sterol stimuli, including activation of protein kinase C, increases in intracellular calcium, inhibition of protein synthesis, and signals generated by the protein synthesis inhibitors CHX and anisomycin, induce LDL receptor gene expression. Thus, transcription of the LDL receptor gene is not only regulated by ambient sterols but also by a variety of influences that govern the various primary response or immediate early genes. These stimuli may play an important role in normal regulation of LDL receptor gene expression.

Gene Expression Regulation, Neoplastic↗

PubMed1993

Dietary fatty acids regulate hepatic low density lipoprotein (LDL) transport by altering LDL receptor protein and mRNA levels.

The concentration of LDL in plasma is strongly influenced by the amount and the type of lipid in the diet. Recent studies in the hamster have shown that dietary fatty acids differentially affect circulating LDL levels primarily by altering receptor-dependent LDL uptake in the liver. To investigate the mechanistic basis of this effect, rates of receptor-dependent LDL transport in the liver were correlated with LDL receptor protein and mRNA levels in hamsters fed safflower oil or coconut oil and varying amounts of cholesterol. Hepatic LDL receptor activity was significantly lower in animals fed coconut oil than in animals fed safflower oil at all levels of cholesterol intake (26, 53, and 61% lower at cholesterol intakes of 0, 0.06, and 0.12%, respectively). These fatty acid-induced changes in hepatic LDL receptor activity were accompanied by parallel changes in hepatic LDL receptor protein and mRNA levels, suggesting that dietary fatty acids regulate the LDL receptor pathway largely at the mRNA level.

Animals↗

PubMed1992

Regulation of hepatic sterol metabolism in the rat. Parallel regulation of activity and mRNA for 7 alpha-hydroxylase but not 3-hydroxy-3-methylglutaryl-coenzyme A reductase or low density lipoprotein receptor.

In vivo regulation of hepatic sterol metabolism was examined in the rat. Sodium cholate markedly suppressed hepatic 7 alpha-hydroxylase mRNA levels and activity when fed to rats on a low cholesterol diet. Sterol balance was maintained solely by decreasing hepatic cholesterol synthesis. Compensatory mechanisms were inadequate when cholate was fed to rats on a high cholesterol diet and massive amounts of cholesterol accumulated in the liver and plasma. Suppression of bile salt synthesis was not responsible since cholate did not suppress 7 alpha-hydroxylase activity when fed to rats on a high cholesterol diet. Moreover, total hepatic low density lipoprotein receptor activity was not suppressed even though liver cholesteryl ester levels were increased more than 350-fold. Changes in 7 alpha-hydroxylase activity were always accompanied by parallel changes in mRNA, whereas mRNA levels for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase were reduced by 50% or less, even when cholesterol synthesis was suppressed by 98%. HMG-CoA reductase and low density lipoprotein receptor activities were regulated independently although mRNA levels for these two proteins were coordinately regulated. These findings indicate that 7 alpha-hydroxylase is controlled by mRNA levels, whereas in vivo cholesterol synthesis is predominantly controlled by posttranscriptional regulation of HMG-CoA reductase activity.

Animals↗

PubMed1992

Differential regulation of the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase, synthase, and low density lipoprotein receptor genes.

The ability of mitogenic stimulation of human T lymphocytes to alter the expression of genes involved in sterol metabolism was examined. Messenger RNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, HMG-CoA synthase, and low density lipoprotein (LDL) receptor were quantified in resting and mitogen-stimulated T lymphocytes by nuclease protection assay. Mitogenic stimulation increased HMG-CoA synthase mRNA levels by 5-fold and LDL receptor by 4-fold when cells were cultured in lipoprotein-depleted medium whereas HMG-CoA reductase gene expression was not significantly increased. When cultures were supplemented with concentrations of low density lipoprotein sufficient to saturate LDL receptors, expression of all three genes was inhibited in resting lymphocytes, as effectively as was noted with fibroblasts. Similarly, LDL down-regulated gene expression in mitogen-activated lymphocytes so that mitogenic stimulation did not increase either HMG-CoA reductase or synthase mRNA levels, although LDL receptor gene expression was enhanced. These results indicate that expression of three of the genes involved in sterol metabolism is differentially regulated by LDL and mitogenic stimulation. Moreover, the increase in rates of endogenous sterol synthesis and the activity of HMG-CoA reductase in mitogen-stimulated T lymphocytes cannot be accounted for by increases in HMG-CoA reductase mRNA levels.

Cholesterol, LDL↗

PubMed1991

Negative regulation of cell proliferation by mevalonate or one of the mevalonate phosphates.

The role of mevalonate and its products in the regulation of cellular proliferation was examined using 6-fluoromevalonate (Fmev), a compound that blocks the conversion of mevalonate pyrophosphate to isopentenyl pyrophosphate. Fmev suppressed DNA synthesis by a variety of transformed and malignant T cell, B cell, and myeloid cell lines. In contrast to results previously reported with mitogen-stimulated human peripheral blood T cell DNA synthesis, low concentrations of low density lipoprotein (LDL) alone could not restore proliferation to these cell lines. The same concentrations of LDL were able to provide sufficient cholesterol and support the growth of all cell lines when mevalonate synthesis was blocked with a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, lovastatin. Fmev-mediated inhibition was totally prevented in some but not all cell lines when the concentration of exogenous LDL was increased 5-10-fold above that required to permit proliferation of lovastatin-blocked cells. Residual HMG-CoA reductase activity of cells cultured with LDL inversely correlated with the restoration of growth to Fmev-blocked cultures. Confirmation of the critical role of HMG-CoA reductase activity and mevalonate synthesis in the inhibition of cellular proliferation by Fmev was obtained by demonstrating that the specific inhibitor of this enzyme, lovastatin, restored proliferation of Fmev-blocked cells. Furthermore, supplementation of cultures with mevalonate, the product of HMG-CoA reductase activity, markedly inhibited proliferation of Fmev-blocked cells. These findings indicate that mevalonate or one of the mevalonate phosphates, which accumulates in Fmev-blocked cells, is a critical negative regulator of cellular proliferation.

Cell Division↗

PubMed1991

Hepatitis B--molecular variants with clinical significance?

Mutations in the DNA of the hepatitis B virus have been discovered and they may have clinical significance. A single nucleotide substitution resulting in a premature stop codon in the pre-core region of the hepatitis B genome is the most common change. The premature stop codon prevents the synthesis of hepatitis B e antigen (HBeAg), a virally encoded protein normally secreted by hepatocytes. The mutant hepatitis B virus was initially discovered in patients who lacked HBeAg in the serum yet had high levels of hepatitis B viral DNA, a marker of active viral replication usually found in association with the continued presence of HBeAg. Other studies demonstrated that the mutant forms were observed with increasing frequency during the successful conversion from HBeAg positivity to anti-hepatitis B e antibody (anti-HBe) positivity. The mutant form of hepatitis B virus was not identified in patients with stable chronic hepatitis B who were positive for HBeAg or in any patients with uncomplicated acute hepatitis B, regardless of the presence of HBeAg or anti-HBe. However, mutant hepatitis B virus was detected in patients with fulminant hepatitis B who lacked both HBeAg and anti-HBe. The lack of HBeAg in the serum therefore may result in a more severe form of acute disease. Together with experimental animal studies of the normal role of HBeAg, these data suggest that serum HBeAg may be associated with immunologic tolerance, whereas clearance of or lack of HBeAg may be associated with an active immunologic response. Future studies are expected to clarify the role of mutant forms of hepatitis B virus in the natural history of hepatitis B infection.

Amino Acid Sequence↗

PubMed1991

A product of mevalonate proximal to isoprenoids is the source of both a necessary growth factor and an inhibitor of cell proliferation.

These studies demonstrate that mevalonate or the mevalonate phosphates play a number of regulatory roles in cellular proliferation. They are not only required for cell growth but are also a source of an inhibitor of cell growth. Endogenous concentrations of mevalonate and the mevalonate phosphates are thus critical determinants of cellular proliferation.

Cell Division↗