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P Morell

Publications and source records attributed to P Morell.

At least 37 records · Page 2Linked to original sources
PubMed1995

Schwann cell ATP-mediated calcium increases in vitro and in situ are dependent on contact with neurons.

Schwann cells freshly isolated from the sciatic nerves of neonatal rats respond to exogenously applied ATP with a rapid increase in cytosolic calcium. This increase in [Ca2+]i is mediated by a P2Y-purinergic pathway (Lyons et al.: J. Neurochem. 63:552-560, 1994) and was measured using the calcium indicator dye, fura-2/AM, and a video-enhanced calcium imaging system. The ability to respond to ATP with increases in intracellular calcium is lost over a period of several days in culture; this loss can be prevented or reversed by application of cAMP analogs in a defined medium. We now demonstrate that the direct contact of Schwann cells with neurons also induces and stabilizes this ATP responsiveness. The induction of ATP responsiveness was observed among all Schwann cells contacting neurites, including those forming myelin, and regardless of whether the source of neurons was dorsal root ganglion neurons or superior cervical ganglion neurons. Approximately 85% of Schwann cells responded to ATP over the time studied (72 d in coculture). Addition of axolemma to Schwann cell cultures did not induce ATP responsiveness. We also examined the ATP responsiveness of Schwann cells in situ (excised nerves) using laser-scanning confocal microscopy and the calcium indicator dye, fluo-3/AM. Schwann cells in intact sciatic nerve segments isolated from neonatal and 16-day-old rats exhibited ATP-mediated [Ca2+]i increases. We conclude that neuronal contact is necessary for the expression of the ATP-mediated calcium responses in Schwann cells and that these responses are independent of myelin formation or maintenance.

Adenosine Triphosphate↗
PubMed1995

NGFR-mRNA expression in sciatic nerve: a sensitive indicator of early stages of axonopathy.

Expression of the low-affinity nerve growth factor receptor (NGFR) in the sciatic nerve (particularly Schwann cells) is high during development but is downregulated upon establishment of the mature axon-Schwann cell relationship. NGFR is re-expressed by Schwann cells if this relationship is altered by degeneration of axons (axotomy) or myelin (tellurium intoxication). To determine the sensitivity of NGFR expression to axonal injury, we have assayed NGFR-mRNA levels in proximal and distal regions of nerves exposed to the axonopathic agents acrylamide and isoniazid, as well as in proximal and distal stumps of axotomized nerves. NGFR-mRNA was elevated in all three models and correlated regionally with sites of axonal perturbation. In distal regions of acrylamide- and isoniazid-intoxicated nerves, NGFR-mRNA was elevated at least 2 days prior to visible signs of axonal degeneration as assayed by morphological techniques utilizing light microscopy. NGFR-mRNA was also elevated in proximal regions of axotomized and acrylamide-intoxicated nerves prior to signs of axonal degeneration. In these models, increased mRNA expression correlated with alterations in the size distribution of axonal cross sections. The common response in all of these situations indicates that NGFR expression, in addition to being a marker for axonal degeneration, is also a sensitive indicator of less profound perturbations in normal axon-Schwann cell interactions, including early stages of axonopathy. We suggest that assay for NGFR-mRNA may be utilized as a rapid and simple method (relative to more labor-intensive morphological methods) to screen for peripheral neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylamide↗
PubMed1995

Cholesterol for synthesis of myelin is made locally, not imported into brain.

We examined whether cholesterol needed for myelin formation is locally synthesized or whether it comes from the circulation. The experimental design was to inject [3H]water and to use incorporation of label into brain cholesterol as a measure of the rate of accumulation of newly synthesized cholesterol in brain. The contribution of the circulation to this labeled cholesterol pool was minimized by repressing liver synthesis of cholesterol with a high cholesterol diet. The rate of accumulation of total cholesterol was calculated from the increasing amounts of sterol in brain regions at successive time intervals during development. Thus, accumulating cholesterol not explained as being newly synthesized (radioactive) could be assumed to have come from the circulation. Long-Evans rats, ranging in age from birth to 35 days, were injected intraperitoneally with [3H]water (0.3-1.0 mCi/g of body weight) and killed 2 h later. The brain was dissected into brainstem, cerebellum, and cerebral hemispheres, and total lipids were extracted. Cholesterol and its precursors were quantified by HPLC. The radioactivity associated with the sterol fractions and the specific activity of body water determined from serum were used to calculate the absolute amount of newly synthesized sterol. The rates of cholesterol synthesis were compared with the rates of accumulation of total cholesterol in each brain region. The rate of accumulation of total sterol (cholesterol and desmosterol) closely followed that of newly synthesized total sterol in all brain regions from the second through the fifth postnatal weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1995

Tellurite specifically affects squalene epoxidase: investigations examining the mechanism of tellurium-induced neuropathy.

A peripheral neuropathy characterized by a transient demyelinating/remyelinating sequence results when young rats are fed a tellurium-containing diet. The neuropathy occurs secondary to a systemic block in cholesterol synthesis. Squalene accumulation suggested the lesion was at the level of squalene expoxidase, a microsomal monooxygenase that uses NADPH cytochrome P450 reductase to receive its necessary reducing equivalents from NADPH. We have now demonstrated directly specificity for squalene epoxidase; our in vitro studies show that squalene epoxidase is inhibited 50% in the presence of 5 microM tellurite, the presumptive in vivo active metabolite. Under these conditions, the activities of other monooxygenases, aniline hydroxylase and benzo(a)pyrene hydroxylase, were inhibited less than 5%. We also present data suggesting that tellurite inhibits squalene epoxidation by interacting with highly susceptible -SH groups present on this monooxygenase. In vivo studies of specificity were based on the compensatory response to feeding of tellurium. Following tellurium intoxication, there was up-regulation of squalene epoxidase activity both in liver (11-fold) and sciatic nerve (fivefold). This induction was a specific response, as demonstrated in liver by the lack of up-regulation following exposure to the nonspecific microsomal enzyme inducer, phenobarbital. As a control, we also measured the microsomal monooxygenase activities of aniline hydroxylase and benzo(a)pyrene hydroxylase. Although they were induced following phenobarbital exposure, activities of these monooxygenases were not affected following tellurium intoxication, providing further evidence of specificity of tellurium intoxication for squalene epoxidase.

Aniline Hydroxylase↗
PubMed1994

Isolation, characterization, and expression of cDNA clones that encode rat UDP-galactose: ceramide galactosyltransferase.

UDP-galactose:ceramide galactosyltransferase (CGT) (EC. 2.4.1.62) catalyzes the final step in the synthesis of galactocerebroside (GalC), a glycosphingolipid found in high amounts in the myelin sheath. Here, the isolation of rat CGT specific cDNA clones is reported. The CGT sequence contains an open reading frame of 1,623 bp which predicts a protein of M(r) 61,126 Da. In transfection experiments the cDNA was found to confer CGT activity to Chinese hamster ovary cells. In rat brain the developmental expression pattern of CGT mRNA was similar to the myelination profile, whereas the sciatic nerve contained high amounts of CGT message over a long developmental period. CGT mRNA expression in the sciatic nerve was found to drop substantially following nerve injury and recover slowly when compared to the expression of mRNAs specific for the predominant myelin-specific proteins. The absolute amounts of CGT message in sciatic nerve and brain were found to be comparable to those that encode the structural proteins of myelin. Except for low amounts in the kidney, the CGT mRNA was not detected in other tissues examined. Southern blot analysis revealed that the CGT protein is likely encoded by a single, relatively large gene.

Amino Acid Sequence↗
PubMed1994

Metabolic turnover of myelin glycerophospholipids.

The apparent half life for metabolic turnover of glycerophospholipids in the myelin sheath, as determined by measuring the rate of loss of label in a myelin glycerophospholipid following radioactive precursor injection, varies with the radioactive precursor used, age of animal, and time after injection during which metabolic turnover is studied. Experimental strategies for resolving apparent inconsistencies consequent to these variables are discussed. Illustrative data concerning turnover of phosphatidylcholine (PC) in myelin of rat brain are presented. PC of the myelin membrane exhibits heterogeneity with respect to metabolic turnover rates. There are at least two metabolic pools of PC in myelin, one with a half life of the order of days, and another with a half life of the order of weeks. To a significant extent biphasic turnover is due to differential turnover of individual molecular species (which differ in acyl chain composition). The two predominant molecular species of myelin PC turnover at very different rates (16:0, 18:1 PC turning over several times more rapidly than 18:0, 18:1 PC). Therefore, within the same membrane, individual molecular species of a phospholipid class are metabolized at different rates. Possible mechanisms for differential turnover of molecular species are discussed, as are other factors that may contribute to a multiphasic turnover of glycerophospholipids.

Animals↗
PubMed1994

Schwann cells exhibit P2Y purinergic receptors that regulate intracellular calcium and are up-regulated by cyclic AMP analogues.

Schwann cells establish close contact with axons during development, and this is maintained throughout life. Signaling by neurotransmitters may play an important role in Schwann cell-axon interaction. Schwann cells were examined for the presence of neuroligland receptors that are linked to increases in levels of cytoplasmic calcium. Schwann cell cultures were prepared from neonatal rat sciatic nerve and, after 0.25, 1, 4, 7, and 14 days in vitro (DIV), loaded with the calcium indicator dye fura 2-AM. The influence of neuroligands on the cytosolic free calcium concentration ([Ca2+]i) was then examined at each time point using a video-based imaging system. Approximately 80-95% of all freshly isolated Schwann cells responded to 10 microM ATP with a three-fold rise in [Ca2+]i. Bradykinin, glutamate, and histamine had no or only partial and inconsistent responses. The ATP-induced calcium response disappeared within 4 DIV. Culturing cells in the presence of cyclic AMP (cAMP) analogues (which induce proliferation and differentiation in vitro) restored the ability of Schwann cells to respond to ATP with increased [Ca2+]i. In the presence of cAMP analogues the extent of recovery of ATP responsiveness was dependent on serum concentration. Fifty to ninety percent of cells regained calcium responsiveness to ATP when grown in medium containing cAMP analogues and 1% serum. These cells also exhibited immunoreactivity to P0 antibody, characteristic of the myelinating lineage. In contrast, only 15-30% of the Schwann cells regained calcium responsiveness when grown in medium containing cAMP analogues and 10% serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1994

Advances in understanding the development of the nervous system.

Over the past several years remarkable progress has been made towards unraveling the complex mechanisms that regulate neuronal development. Because the end results of abnormalities in brain development are often developmental disabilities, it is timely to review several recent advances in the field of neurobiology. This review, with contributions from several co-authors, provides a synopsis of breakthroughs from the fields of embryology, cell biology, and molecular genetics that hold promise for exciting clinical application. This article is arranged to reflect the stages of normal development. Understanding the mechanisms underlying neuronal induction, regional specification, neuronal specification, migration, axonal growth, neurotrophic factors, and myelination should clarify the pathophysiology of numerous neurological disorders, and provide new insights into their treatment.

Animals↗
PubMed1994

Gene expression during tellurium-induced primary demyelination.

A compound may be "developmentally neurotoxic" because it interferes with a metabolic step exclusively or preferentially expressed during development in a particular class of neural cells. The initial metabolic specificity is often complicated by: (1) secondary responses in the affected cells, (2) involvement of other functionally-related cell types, and (3) the presence of compensatory and/or regenerative responses. In this context we study tellurium, which systemically blocks cholesterol biosynthesis at the squalene epoxidase step. Because of the high demand in developing peripheral nerves for newly synthesized cholesterol required for myelin assembly, this metabolic block leads to demyelination of the sciatic nerve. This insult is confounded by the fact that the myelin-forming Schwann cells do not upregulate their cholesterol biosynthetic pathway. This is contrary to expectations; liver (the main source of cholesterol for many tissues outside the nervous system) upregulates synthesis of cholesterol and overcomes the metabolic block. The shortage of cholesterol in Schwann cells results in an immediate secondary response down-regulation of steady-state mRNA levels for specific myelin proteins. Remyelination occurs after cessation of tellurium exposure. This model of primary demyelination allows study of Schwann-cell specific responses during the processes of myelin breakdown and subsequent steps leading to remyelination, without the complications of axonal degeneration and regeneration. Because tellurium specifically blocks the synthesis of a major required membrane component, it is also well suited for examining the coordinate control of membrane synthesis and assembly at the genomic level.

Animals↗
PubMed1994

Sources of cholesterol for kidney and nerve during development.

Rats were injected intraperitoneally with [3H]water; 2 h later, they were killed, dissected, and cholesterol was isolated from several tissues. Measurement of incorporated radioactivity allowed for calculation of the absolute amount of newly synthesized cholesterol appearing in a tissue. We determined the daily rate of synthesis of cholesterol in the sciatic nerve and kidney of rats at 10 time points between birth and 35 days of age. We compared this to the daily rate of accumulation of total cholesterol. For the sciatic nerve, total accumulation of cholesterol during development was always matched by accumulation of newly synthesized cholesterol, indicating that sciatic nerve synthesizes all of its own cholesterol. This was so independently of whether, at weaning, animals were placed on a cholesterol-free diet or a 2% cholesterol-containing diet. In contrast, in kidney, during the suckling period, only 25% of the accumulated cholesterol was newly synthesized; the remainder came from the circulation. Upon weaning to a 2% cholesterol-containing diet, there was increased local synthesis of cholesterol in kidney, so that within a few days about 50% was locally synthesized. If, however, the animals were weaned onto a cholesterol-free diet, there appeared to be further up-regulation of cholesterol biosynthesis in kidney; now all of the cholesterol accumulating was accounted for by that newly synthesized. Thus, the nerve is invariant with respect to self sufficiency for cholesterol; the kidney changes in this regard during development and as a function of diet.

Animals↗
PubMed1992

Individual molecular species of phosphatidylcholine and phosphatidylethanolamine in myelin turn over at different rates.

Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) of the myelin membrane exhibit heterogeneity with respect to metabolic turnover rate (Miller, S. L., Benjamins, J. A., and Morell, P. (1977) J. Biol. Chem. 252, 4025-4037). To test the hypothesis that this is due to differential turnover of individual molecular species (which differ in acyl chain composition), we have examined the relative turnover of individual molecular species of myelin PC and PE. Phospholipids were labeled by injection of [2-3H]glycerol into the brains of young rats. Myelin was isolated at 1, 15, and 30 days post-injection, lipids were extracted, and phospholipid classes were separated by thin-layer chromatography. The PC and PE fractions were hydrolyzed with phospholipase C, and the resulting diacylglycerols were dinitrobenzoylated and fractionated by reverse-phase high performance liquid chromatography. The distribution of radioactivity among individual molecular species was determined. The labeled molecular species of myelin PC were 16:0-16:0, 16:0-18:0, 16:0-18:1, and 18:0-18:1, with most of the label present in 16:0-18:1 and 18:0-18:1. Changes in distribution of label with time after injection indicated that 16:0-18:1 turned over more rapidly than 18:0-18:1. The labeled molecular species of myelin PE were 18:0-20:4, 18:1-18:1, 16:0-18:1, 18:0-18:2, and 18:0-18:1. As with myelin PC, 16:0-18:1 (and 18:1-18:1) turned over more rapidly than 18:0-18:1. The relative turnover of individual molecular species of PC in the microsomal fraction from forebrain was also examined. The molecular species profile was different from myelin PC, but again, 16:0-18:1 turned over more rapidly than the other molecular species. Thus, within the same membrane, individual molecular species of a phospholipid class are metabolized at different rates. Comparison of our results with previous studies of turnover of molecular classes of phospholipids indicates that in addition to polar head group composition (Miller et al., 1977), fatty acid composition is very important in determining the metabolic fate of a phospholipid.

Animals↗
PubMed1992

Acrylamide exposure preferentially impairs axonal transport of glycoproteins in myelinated axons.

The right L5 dorsal root ganglion of adult rats exposed to acrylamide (40 mg/kg body weight/day for nine consecutive days) was injected with either [3H]methionine or [3H]glucosamine. After allowing incorporation into macromolecules and axonal transport to proceed for 5 hr, the distribution of radioactivity in cross sections and longitudinal sections of sciatic nerve was determined by autoradiography. Control and treated animals showed no difference in distribution of label within the sciatic nerve with respect to rapidly transported proteins labelled with [3H]methionine. In control animals the distribution of rapidly transported glycoproteins labelled with [3H]glucosamine was similar to that found for [3H]methionine-labelled proteins. In contrast, acrylamide-exposed rats had a very different distribution of labelled glycoproteins; there was a marked paucity of label in the myelinated axons. We interpret this result as indicating that acrylamide preferentially inhibits glycosylation or axonal transport of glycoproteins in neurons bearing myelinated axons.

Acrylamide↗
PubMed1992

Neurofilament and tubulin mRNA expression in Schwann cells.

Feeding of elemental tellurium to weanling rats blocks synthesis of cholesterol (a major component of myelin), and causes demyelination of the sciatic nerve. Expression of mRNA for myelin-specific genes in Schwann cells is downregulated. We now demonstrate specificity for Schwann cell injury in that expression of mRNAs for neurofilament subunits and for class II beta-tubulin (parameters sensitive to axonal injury) is unaltered in neurons of the dorsal root ganglia. An unexpected result was that in tellurium-treated rats there was marked upregulation of expression of mRNAs coding for the light and medium neurofilament subunits ("neuron-specific" proteins) as well as that for class II beta-tubulin (the major neuronal beta-tubulin isotype) in Schwann cells. Expression of these "neuronal" mRNA species was also detected in distal stumps of transected nerves at times when Schwann cells were undergoing dedifferentiation.

Animals↗
PubMed1992

Bradykinin stimulates arachidonic acid release through the sequential actions of an sn-1 diacylglycerol lipase and a monoacylglycerol lipase.

In cultured dorsal root ganglion (DRG) neurons prelabeled with [3H]arachidonic acid [( 3H]AA), bradykinin (BK) stimulation resulted in increased levels of radioactive diacylglycerol, monoacylglycerol, and free AA. The transient increases in content of radioactive diacylglycerol and monoacylglycerol preceded the increase in level of free AA, suggesting the contribution of a diacylglycerol lipase pathway to AA release. An analysis of the molecular species of diacylglycerols in unstimulated cultures revealed the presence of two primary [3H]AA-containing species, 1-palmitoyl-2-arachidonoyl and 1-stearoyl-2-arachidonoyl diacylglycerol. BK stimulation resulted in a preferential increase in content of 1-stearoyl-2-arachidonoyl diacylglycerol. When DRG cultures were labeled with [3H]stearic acid, treatment with BK increased the amount of label in diacylglycerol and free stearic acid, but not in monoacylglycerol. This result suggested that AA release occurred through the successive actions of an sn-1 diacylglycerol lipase and monoacylglycerol lipase. Other data supporting a diacylglycerol lipase pathway was the significant inhibition of [3H]AA release and consequent accumulation of diacylglycerol by RG 80267, which preferentially inhibits diacylglycerol lipase. Analysis of the molecular species profiles of individual phospholipids in DRG neurons indicated that phosphoinositide hydrolysis may account for a significant portion of the rapid increase in content of 1-stearoyl-2-arachidonoyl diacylglycerol. We were unable to obtain evidence that the phospholipase A2 pathway makes a significant contribution to BK-stimulated AA release in DRG cultures. Under our assay conditions there were no BK-stimulated increases in levels of radioactive lysophosphatidylinositol, lysophosphatidylcholine, or lysophosphatidylethanolamine in cultures prelabeled with [3H]inositol, [3H]choline, or [3H]-ethanolamine, respectively.

Animals↗
PubMed1992

Primary demyelination induced by exposure to tellurium alters Schwann cell gene expression: a model for intracellular targeting of NGF receptor.

Exposure of developing rats to tellurium results in a highly synchronous segmental demyelination of peripheral nerves with sparing of axons; this demyelination is followed closely by a period of rapid remyelination. Demyelination occurs subsequent to a tellurium-induced block in the synthesis of cholesterol, the major myelin lipid. We utilized the techniques of Northern blotting, in situ hybridization, and immunocytochemistry to examine temporal alterations in Schwann cell gene expression related to demyelination and remyelination. Tellurium-induced demyelination is associated with downregulation of myelin protein expression and a corresponding upregulation of NGF receptor (NGF-R) and glial fibrillary acidic protein (GFAP) expression. Steady-state mRNA levels (expressed on a "per nerve" basis) for P0, the major myelin protein, were decreased by about 50% after 5 d of tellurium exposure, while levels of mRNA for NGF-R and GFAP were markedly increased (about 15-fold). In situ hybridization of teased fibers suggested that the increase in steady-state mRNA levels for NGF-R was primarily associated with demyelinated internodes and not with adjacent unaffected internodes. Although P0 message was almost totally absent from demyelinating internodes, it was also reduced in normal-appearing internodes as well. This suggests that limiting the supply of a required membrane component (cholesterol) may lead to partial downregulation of myelin gene expression in all myelinating Schwann cells. In partially demyelinated internodes, NGF-R and GFAP immunofluorescence appeared largely confined to the demyelinated regions. This suggests specific targeting of these proteins to local areas of the Schwann cell where there is myelin loss. These results demonstrate that demyelination is associated with reversion of the affected Schwann cells to a precursor cell phenotype. Because axons remain intact, our results suggest that these changes in Schwann cell gene expression do not require input from a degenerating axon, but instead may depend on whether concerted synthesis of myelin is occurring.

Animals↗
PubMed1991

Primary demyelination induced by exposure to tellurium alters mRNA levels for nerve growth factor receptor, SCIP, 2',3'-cyclic nucleotide 3'-phosphodiesterase, and myelin proteolipid protein in rat sciatic nerve.

Weanling rats fed a diet containing tellurium develop a peripheral neuropathy characterized by a highly synchronous primary demyelination; this demyelination is followed closely by a period of rapid remyelination. The demyelination is related to the inhibition of squalene epoxidase activity, which results in a block in cholesterol synthesis. Expression of mRNA for the major structural proteins of PNS myelin, myelin basic protein and P0, is coordinately down-regulated during the demyelinating phase and then up-regulated during the remyelinating phase (Toews et al., J. Neurosci. Res., 26 (1990) 501-507). We now report tellurium-induced alterations in gene expression for several proteins which are not major structural components of myelin in the peripheral nervous system. Expression of mRNA for nerve growth factor receptor in sciatic nerve was very low in control animals, but was markedly up-regulated after 3-5 days of exposure to tellurium, a time corresponding to the beginning of demyelination. Levels remained elevated during the subsequent period of remyelination. Expression of mRNA for SCIP (a presumptive transcription factor) was also up-regulated in sciatic nerve following tellurium exposure, with a time course similar to that for nerve growth factor receptor. When examined as a fraction of total RNA, steady-state mRNA levels for 2',3'-cyclic nucleotide 3'-phosphodiesterase and the myelin proteolipid protein were decreased during the demyelinating phase; however, this decrease could be largely accounted for by increased levels of total RNA. When analyzed on a 'per nerve' basis, steady-state mRNA levels for these two proteins were actually increased about 2-fold by 9 days after beginning tellurium exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1991

Tellurium blocks cholesterol synthesis by inhibiting squalene metabolism: preferential vulnerability to this metabolic block leads to peripheral nervous system demyelination.

Inclusion of 1.1% elemental tellurium in the diet of postweanling rats produces a peripheral neuropathy due to a highly synchronous primary demyelination of sciatic nerve; this demyelination is followed closely by remyelination. Sciatic nerves from animals fed tellurium for various times were removed and incubated ex vivo for 1 h with [14C]acetate, and radioactivity incorporated into individual lipid classes was determined. In nerves from rats exposed to tellurium, there was a profound and selective block in the conversion of radioactive acetate to cholesterol. Another radioactive precursor, [3H]water, gave similar results. We suggest that tellurium feeding inhibits squalene epoxidase activity and that the consequent lack of cholesterol destabilizes myelin, thereby causing destruction of the larger internodes. Ex vivo incubation experiments were also carried out with liver slices. As with nerve, tellurium feeding caused accumulation in squalene of label from radioactive acetate, whereas labeling of cholesterol was greatly inhibited. Unexpectedly, however, incorporation of label from [3H]water into both squalene and cholesterol was increased. Relevant is the demonstration that liver was the primary site of bulk accumulation of squalene, which accounted for 10% of liver dry weight at 5 days. Thus, accumulation of squalene (and other mechanisms, possibly including up-regulation of cholesterol biosynthetic pathways) drives squalene epoxidase activity at normal levels in liver even in the presence of inhibitors of this enzyme. This is reflected by continuing incorporation of [3H]water into cholesterol; incorporation of this precursor takes place at many of the postsqualene biosynthetic steps for sterol formation. [14C]Acetate entering the sterol pathway before squalene in liver is greatly diluted in specific activity when it reaches the large squalene pool, and thus increased squalene epoxidase activity does not transfer significant 14C label to sterols. In contrast to the situation with liver, synthesis of sterols is markedly depressed in sciatic nerve, and squalene does not accumulate to high levels.

Acetates↗