Biomedical subjects

J C Lai

Publications and source records attributed to J C Lai.

At least 55 records · Page 3Linked to original sources

PubMed1992

Oxidative metabolism in neuronal and non-neuronal mitochondria.

Methodological advances have allowed the isolation of two populations of synaptic (SM and SM2) and two populations of nonsynaptic (A and B) mitochondria from rat forebrain. All four populations of brain mitochondria are metabolically active and essentially free from nonmitochondrial contaminants. They (SM, SM2, A, and B) can oxidize a variety of substrates; the best substrate is pyruvate. With pyruvate as the substrate, the respiratory control ratios (i.e., state 3/state 4) in all four populations are routinely > 6. Results from numerous enzyme activity measurements provide strong support for the hypothesis that brain mitochondria are very heterogeneous with respect to their enzyme contents and that the enzymatic activities in a particular population of mitochondria, be they synaptic or nonsynaptic, differ from those in another population of mitochondria derived from either the same or another brain region. The major methodological advances in brain mitochondrial isolation greatly facilitate metabolic studies. For example, we have demonstrated that the K+ stimulation of brain mitochondrial pyruvate oxidation is mediated through a K(+)-induced elevation of the activation state of the pyruvate dehydrogenase complex and the K+ stimulation of the flux through the pyruvate dehydrogenase complex. Our previous and ongoing studies using primary cultures of hypothalamic neurons and astrocytes are consistent with the proposal that brain cells are heterogeneous with respect to their capabilities in energy metabolism. I can envisage that in the no-so-distant future, one could adapt these preparations of cells as the starting material for the isolation of mitochondria of known cellular origin for metabolic studies.

Animals↗

PubMed1991

Neurotoxicity of ammonia and fatty acids: differential inhibition of mitochondrial dehydrogenases by ammonia and fatty acyl coenzyme A derivatives.

In several metabolic encephalopathies, hyperammonemia and organic acidemia are consistently found. Ammonia and fatty acids (FAs) are neurotoxic: previous workers have shown that ammonia and FAs can act singly, in combination, or synergistically, in inducing coma in experimental animals. However, the biochemical mechanisms underlying the neurotoxicity of ammonia and FAs have not been fully elucidated. FAs are normally converted to their corresponding CoA derivatives (CoAs) once they enter cells and it is known that these fatty acyl CoAs can alter intermediary metabolism. The present study was initiated to determine the effects of ammonia and fatty acyl CoAs on brain mitochondrial dehydrogenases. At a pathophysiological level (2 mM), ammonia is a potent inhibitor of brain mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC). Only at toxicological levels (10-20 mM) does ammonia inhibit brain mitochondrial NAD(+)- and NADP(+)- linked isocitrate dehydrogenase (NAD-ICDH, NADP-ICDH), and NAD(+)-linked malate dehydrogenase (MDH) and liver mitochondrial NAD-ICDH. Butyryl- (BCoA), octanoyl- (OCoA), and palmitoyl (PCoA) CoA were potent inhibitors of brain mitochondrial KGDHC, with IC50 values of 11, 20, and 25 microM, respectively; moreover, the inhibitory effect of fatty acyl CoAs and ammonia were additive. At levels of 250 microM or higher, both OCoA (IC50 = 1.15 mM) and PCoA (IC50 = 470 microM) inhibit brain mitochondrial NADP-ICDH; only at higher levels (0.5-1 mM) does BCoA inhibit this enzyme (by 30-45%). Much less sensitive than KGDHC and NADP-ICDH, brain mitochondrial NAD-ICDH is only inhibited by 1 mM BCoA, OCoA, and PCoA by 22%, 35%, and 44%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyl Coenzyme A↗

PubMed1991

Effects of chronic manganese treatment on rat brain regional sodium-potassium-activated and magnesium-activated adenosine triphosphatase activities during development.

The effects of chronic manganese (Mn) treatments (1 and 10 mg MnCl2.4H2O per ml of drinking water) from conception onwards on brain regional development of sodium-potassium-activated and magnesium-activated adenosine triphosphatases (Na-K-ATPase and Mg-ATPase) were studied. The activities of these enzymes were determined in hypothalamus, cerebellum, pons and medulla, striatum, midbrain and cerebral cortex (which included the hippocampus) of Mn-treated and age-matched control rats at 5 postnatal ages. Both ATPase activities doubled in most brain regions between day 5 and day 20 postnatal. In pons and medulla, striatum, midbrain, and cerebral cortex, adult levels of both enzymatic activities were attained by day 20 postnatal. Na-K-ATPase activities transiently increased in the midbrain (+25%) at day 12 with the lower Mn dose and in the cerebral cortex (+31%) at day 20 with the higher Mn dose. With the higher Mn dose only, Mg-ATPase activities were increased in the hypothalamus (+20%) at day 12 and in the pons and medulla (+22%) at day 20 but were decreased in the pons and medulla (-20%) at day 60. Thus, only transient changes in enzymatic activities were observed despite dose-dependent increases in the brain levels of Mn resulting from the Mn treatment. A hypothesis regarding the role of early but transient changes in brain metabolism in the pathogenesis of the initial psychotic symptoms in Mn intoxication was proposed and discussed in relation to several other observations of a similar nature.

Age Factors↗

PubMed1990

High-affinity transport of glutathione is part of a multicomponent system essential for mitochondrial function.

Glutathione, an essential cellular antioxidant required for mitochondrial function, is not synthesized by mitochondria but is imported from the cytosol. Rat liver mitochondria have a multicomponent system that underlies the remarkable ability of mitochondria to take up and retain glutathione. At external glutathione levels of less than 1 mM, glutathione is transported into the mitochondrial matrix by a high-affinity component (Km, approximately 60 microM; V max, approximately 0.5 nmol/min per mg of protein), which is saturated at levels of 1-2 mM and stimulated by ATP. Another component has lower affinity (Km, approximately 5.4 mM; Vmax, approximately 5.9 nmol/min per mg of protein) and is stimulated by ATP and ADP. Both components are inhibited by carbonylcyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), glutamate, and ophthalmic acid. Increase of extramitochondrial glutathione promotes uptake and exchange; the intermembranous space seems to function as a recovery zone that promotes efficient recycling of matrix glutathione. The findings are in accord with in vivo data showing that (i) rapid exchange occurs between mitochondrial and cytosolic glutathione, (ii) lowering of cytosolic glutathione levels (produced by administration of buthionine sulfoximine) decreases export of glutathione from mitochondria to cytosol, and (iii) administration of glutathione esters increases glutathione levels in mitochondria more than those in the cytosol.

Animals↗

PubMed1990

Acetylcholinesterase and neuropathy target esterase in chickens treated with acephate.

Reports that near-lethal doses of the pesticide methamidophos (O,S-dimethyl phosphoramidothioate) caused a delayed neurotoxicity (OPIDN) in humans and that another phosphoramidate, isofenphos, caused OPIDN in the hen at high doses, prompted a study of the abilities of acephate (O,S-dimethyl acetylphosphoramidothioate) to inhibit brain acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in vivo. Hens were treated orally with 5-700 mg/kg of acephate, or im with 50-200 micrograms/kg of diisopropyl-fluorophosphate (DFP, positive control) and sacrificed 24 hr later. Brain homogenates were assayed for AChE as an estimate of acute toxicity, for NTE to indicate acephate's potential to cause OPIDN, and for residues of acephate and its metabolite methamidophos. A range finding study confirmed the LD50 level for acephate was approximately 800 mg/kg. Regression analyses indicated an ID50 (a dose that inhibits 50% of activity) for acephate inhibition of AChE of 10 mg/kg and an extrapolated ID50 for inhibition of NTE of 1300 mg/kg, almost twice the LD50. In contrast, ID50 values for DFP were similar for AChE (146 micrograms/kg) and NTE (132 micrograms/kg). Brain methamidophos levels were 10 to 16 percent of the total acephate plus methamidophos brain concentration. The lower the dose of acephate, the higher was the relative percentage of methamidophos. The results show acephate is a more potent inhibitor of AChE than it is of NTE in hens and suggest it would be difficult to administer a single dose of acephate sufficient to cause OPIDN without killing the animal.

Animals↗

PubMed1989

Glutathione is present in high concentrations in cultured astrocytes but not in cultured neurons.

The levels of the antioxidants, glutathione and ascorbate were measured in primary cultures of murine astrocytes and neurons. The concentration of glutathione (reduced, GSH + oxidized, GSSG) was high in cultured, differentiated (i.e. treated with dBcAMP) and undifferentiated (i.e. untreated) astrocytes: approximately 25 (n = 2) and 16.0 +/- 5.0 (n = 7) nmol/mg protein, respectively. In contrast, glutathione levels in neurons were low: less than or equal to 1.0 (n = 7) nmol/mg protein. Ascorbate could not be detected (less than 2 nmol/mg protein) in either cell type. The apparent lack of defense mechanisms against oxidative stress may in part account for the 'fragility' of neurons in culture. The physiological implications of glutathione compartmentation in brain are discussed.

Animals↗

PubMed1989

Effect of orally administered L-carnitine on blood ammonia and L-carnitine concentrations in portacaval-shunted rats.

L-Carnitine (16 mmoles per kg, injected intraperitoneally) is reported to protect mice against subsequent injection of ammonium acetate given at the unprotected LD100. The present studies in rats show a variable protective effect of L-carnitine (16 mmoles per kg) administered 1 hr prior to an LD100 dose of ammonium acetate. Survival ranged from 100% to 35%. In two experiments, protection was highly significant; in a third experiment, L-carnitine did not protect against death but did significantly prolong time to death. Although the cause of this variability is not known, the data establish the protective effect in rats of L-carnitine given 1 hr before ammonium acetate. D-Carnitine and deoxycarnitine, chemically related analogs unable to substitute for L-carnitine metabolically, are without protective effect. The protective effect of L-carnitine is short-lived and is, for example, completely lost if ammonium acetate is given 24 hr after L-carnitine administration. In contrast, the free carnitine content of brain rises slowly but continuously for at least 24 hr following a single dose of L-carnitine. The observation that protection from ammonia toxicity is not correlated with brain carnitine levels strongly suggests a major peripheral component to the protective effect. Chronically hyperammonemic (portacaval-shunted) rats were found to have significantly depressed total and free carnitine levels in blood compared to normal and sham-operated controls. The hypocarnitinemia, but not the hyperammonemia, was completely reversed in portacaval-shunted rats given drinking water containing 10 mM L-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗

PubMed1989

Differential effects of ammonia and beta-methylene-DL-aspartate on metabolism of glutamate and related amino acids by astrocytes and neurons in primary culture.

The effects of ammonium chloride (3 mM) and beta-methylene-DL-aspartate (BMA; 5 mM) (an inhibitor of aspartate aminotransferase, a key enzyme of the malate-aspartate shuttle (MAS] on the metabolism of glutamate and related amino acids were studied in primary cultures of astrocytes and neurons. Both ammonia and BMA inhibited 14CO2 production from [U-14C]- and [1-14C]glutamate by astrocytes and neurons and their effects were partially additive. Acute treatment of astrocytes with ammonia (but not BMA) increased astrocytic glutamine. Acute treatment of astrocytes with ammonia or BMA decreased astrocytic glutamate and aspartate (both are key components of the MAS). Acute treatment of neurons with ammonia decreased neuronal aspartate and glutamine and did not apparently affect the efflux of aspartate from neurons. However, acute BMA treatment of neurons led to decreased neuronal glutamate and glutamine and apparently reduced the efflux of aspartate and glutamine from neurons. The data are consistent with the notion that both ammonia and BMA may inhibit the MAS although BMA may also directly inhibit cellular glutamate uptake. Additionally, these results also suggest that ammonia and BMA exert differential effects on astroglial and neuronal glutamate metabolism.

Amino Acids↗

PubMed1988

Pyruvate dehydrogenase complex is inhibited in calcium-loaded cerebrocortical mitochondria.

An impairment of mitochondrial functions as a result of Ca-loading may be one of the significant events that lead to neuronal death after an ischemic insult. To assess the metabolic consequences of excess Ca on brain mitochondria, pyruvate oxidation was studied in isolated cerebrocortical mitochondria loaded with Ca in vitro. The flux of pyruvate dehydrogenase complex (PDHC) [( 1-14C]pyruvate decarboxylation) was inhibited as the mitochondria accumulated excess Ca under the conditions tested: the inhibition in state 3 (i.e., in the presence of added ADP) was greater than in state 4 (i.e., in the absence of added adenine nucleotides). In state 4, the inhibition of the PDHC flux was accompanied by a similar reduction of the in situ activity of PDHC, indicating a change in PDHC phosphorylation. In state 3, the inhibition of the PDHC flux was greater than the corresponding decrease of the in situ PDHC activity. Thus, mechanisms other than the phosphorylation of PDHC might also contribute to the inhibition of pyruvate oxidation. Measurement of PDHC enzymatic activity in vitro indicated that PDHC, similar to alpha-ketoglutarate dehydrogenase complex, was inhibited by millimolar levels of Ca. This observation suggests that PDHC may also be inhibited non-covalently in Ca-loaded mitochondria in a manner similar to that of alpha-ketoglutarate dehydrogenase complex.

Animals↗

PubMed1987

The effect of 2-oxoglutarate or 3-hydroxybutyrate on pyruvate dehydrogenase complex in isolated cerebrocortical mitochondria.

The oxidation of pyruvate is mediated by the pyruvate dehydrogenase complex (PDHC; EC 1.2.4.1, EC 2.3.1.12 and EC 1.6.4.3) whose catalytic activity is influenced by phosphorylation and by product inhibition. 2-Oxoglutarate and 3-hydroxybutyrate are readily utilized by brain mitochondria and inhibit pyruvate oxidation. To further elucidate the regulatory behavior of brain PDHC, the effects of 2-oxoglutarate and 3-hydroxybutyrate on the flux of PDHC (as determined by [1-14C]pyruvate decarboxylation) and the activation (phosphorylation) state of PDHC were determined in isolated, non-synaptic cerebro-cortical mitochondria in the presence or absence of added adenine nucleotides (ADP or ATP). [1-14C]Pyruvate decarboxylation by these mitochondria is consistently depressed by either 3-hydroxybutyrate or 2-oxoglutarate in the presence of ADP when mitochondrial respiration is stimulated. In the presence of exogenous ADP, 3-hydroxybutyrate inhibits pyruvate oxidation mainly through the phosphorylation of PDHC, since the reduction of the PDHC flux parallels the depression of PDHC activation state under these conditions. On the other hand, in addition to the phosphorylation of PDHC, 2-oxoglutarate may also regulate pyruvate oxidation by product inhibition of PDHC in the presence of 0.5 mM pyruvate plus ADP or 5 mM pyruvate alone. This conclusion is based upon the observation that 2-oxoglutarate inhibits [1-14C]pyruvate decarboxylation to a much greater extent than that predicted from the PDHC activation state (i.e. catalytic capacity) alone. In conjunction with the results from our previous study (Lai, J. C. K. and Sheu, K.-F. R. (1985) J. Neurochem. 45, 1861-1868), the data of the present study are consistent with the notion that the relative importance of the various mechanisms that regulate brain and peripheral tissue PDHCs shows interesting differences.

3-Hydroxybutyric Acid↗

PubMed1987

Inhibition of lactate production in rat brain extracts and synaptosomes by 3-[4-(reduced 3-pyridine aldehyde-adenine dinucleotide)]-pyruvate.

In basic solutions, pyruvate enolizes and reacts (through its 3-carbon) with the 4-carbon of the nicotinamide ring of NAD+, yielding an NAD-pyruvate adduct in which the nicotinamide ring is in the reduced form. This adduct is a strong inhibitor of lactate dehydrogenase, presumably because it binds simultaneously to the NADH and pyruvate sites. The potency of the inhibition, however, is muted by the adduct's tendency to cyclize to a lactam. We prepared solutions of the pyruvate adduct of NAD+ and of NAD+ analogues in which the -C(O)NH2 of NAD+ was replaced with -C(S)NH2, -C(O)CH3, and -C(O)H. Of the four, only the last analogue, 3-[4-(reduced 3-pyridine aldehyde-adenine dinucleotide)]-pyruvate (RAP) cannot cyclize and it was found to be the most potent inhibitor of beef heart and rat brain lactate dehydrogenases. The inhibitor binds very tightly to the NADH site (Ki approximately 1 nM for the A form). Even at high concentrations (20 microM), RAP had little or no effect on rat brain glyceraldehyde-3-phosphate, pyruvate, alpha-ketoglutarate, isocitrate, soluble and mitochondrial malate, and glutamate dehydrogenases. The glycolytic enzymes, hexokinase and phosphofructokinase, were similarly unaffected. RAP strongly inhibited lactate production from glucose in rat brain extracts but was less effective in inhibiting lactate production from glucose in synaptosomes.

Animals↗

PubMed1987

[13N]cisplatin PET to assess pharmacokinetics of intra-arterial versus intravenous chemotherapy for malignant brain tumors.

The biodistribution, blood clearance, and in vivo transformation of cisplatin (cisdiaminedichloroplatinum, DDP) were studied in rats using 13N-labeled and unlabeled DDP. Following the i.v. injection of [13N]DDP, virtually no 13N activity was detected in brain tissue, and no measurable amount of the 13N label was displaced from [13N]DDP. Based on these results, [13N]DDP/positron emission tomographic (PET) scans were performed in two glioblastoma patients undergoing Phase II intra-arterial (i.a.) DDP chemotherapy: [13N]DDP was infused i.v. over 13-15 min, during which time serial PET scans were obtained. One hour later, [13N]DDP mixed with cold DDP (100 mg/m2 therapeutic dose) was infused at the same rate i.a., and a second sequence of PET scans was acquired. The pharmacologic advantage of i.a. administration was calculated as the ratio of integrated tumor/brain count ratios for the i.a. and i.v. studies. Our preliminary results demonstrate the feasibility of quantifying the pharmacologic advantage of i.a. DDP chemotherapy in individual brain tumor patients using [13N]DDP and PET.

Animals↗

PubMed1986

The subcellular localization of glutamate dehydrogenase (GDH): is GDH a marker for mitochondria in brain?

Glutamate dehydrogenase (GDH, EC 1.4.1.2) has long been used as a marker for mitochondria in brain and other tissues, despite reports indicating that GDH is also present in nuclei of liver and dorsal root ganglia. To examine whether GDH can be used as a marker to differentiate between mitochondria and nuclei in the brain, we have measured GDH by enzymatic activity and on immunoblots in rat brain mitochondria and nuclei which were highly enriched by density-gradient centrifugation methods. The activity of GDH was enriched in the nuclear fraction as well as in the mitochondrial fraction, while the activities of other "mitochondrial" enzymes (fumarase, NAD-isocitrate dehydrogenase and pyruvate dehydrogenase complex) were enriched only in the mitochondrial fraction. Immunoblots using polyclonal antibodies against bovine liver GDH confirmed the presence of GDH in the rat brain nuclear and mitochondrial fractions. The GDH in these two subcellular fractions had a very similar molecular weight of 56,000 daltons. The mitochondrial and nuclear GDH differed, however, in their susceptibility to solubilization by detergents and salts. The mitochondrial GDH could be solubilized by extraction with low concentrations of detergents (0.1% Triton X-100 and 0.1% Lubrol PX), while the nuclear GDH could be solubilized only by elevated concentrations of detergents (0.3% each) plus KCl (greater than 150 mM). Our results indicate that GDH is present in both nuclei and mitochondria in rat brain. The notion that GDH may serve as a marker for mitochondria needs to be re-evaluated.

Animals↗

PubMed1986

[3H]spiperone and [3H]quinuclidinyl benzilate binding in striatal membranes from rats chronically treated with manganese chloride throughout development and for over two years.

Chronic treatment of rats with manganese (1 mg MnCl2 X 4H2O per ml of drinking water) from conception till adulthood only slightly decreased [3H]spiperone binding in striatal membranes whereas [3H]quinuclidinyl benzilate binding was not affected. The age-related decreases in dopaminergic and muscarinic cholinergic receptor binding in striatal membranes were not affected by the life-span manganese treatment.

Age Factors↗

PubMed1986

Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors.

The substrate and cofactor requirements and some kinetic properties of the alpha-ketoglutarate dehydrogenase complex (KGDHC; EC 1.2.4.2, EC 2.3.1.61, and EC 1.6.4.3) in purified rat brain mitochondria were studied. Brain mitochondrial KGDHC showed absolute requirement for alpha-ketoglutarate, CoA and NAD, and only partial requirement for added thiamine pyrophosphate, but no requirement for Mg2+ under the assay conditions employed in this study. The pH optimum was between 7.2 and 7.4, but, at pH values below 7.0 or above 7.8, KGDHC activity decreased markedly. KGDHC activity in various brain regions followed the rank order: cerebral cortex greater than cerebellum greater than or equal to midbrain greater than striatum = hippocampus greater than hypothalamus greater than pons and medulla greater than olfactory bulb. Significant inhibition of brain mitochondrial KGDHC was noted at pathological concentrations of ammonia (0.2-2 mM). However, the purified bovine heart KGDHC and KGDHC activity in isolated rat heart mitochondria were much less sensitive to inhibition. At 5 mM both beta-methylene-D,L-aspartate and D,L-vinylglycine (inhibitors of cerebral glucose oxidation) inhibited the purified heart but not the brain mitochondrial enzyme complex. At approximately 10 microM, calcium slightly stimulated (by 10-15%) the brain mitochondrial KGDHC. At concentrations above 100 microM, calcium (IC50 = 1 mM) inhibited both brain mitochondrial and purified heart KGDHC. The present results suggest that some of the kinetic properties of the rat brain mitochondrial KGDHC differ from those of the purified bovine heart and rat heart mitochondrial enzyme complexes. They also suggest that the inhibition of KGDHC by ammonia and the consequent effect on the citric acid cycle fluxes may be of pathophysiological and/or pathogenetic importance in hyperammonemia and in diseases (e.g., hepatic encephalopathy, inborn errors of urea metabolism, Reye's syndrome) where hyperammonemia is a consistent feature. Brain accumulation of calcium occurs in a number of pathological conditions. Therefore, it is possible that such a calcium accumulation may have a deleterious effect on KGDHC activity.

Ammonia↗

PubMed1985

Differences in some of the metabolic properties of mitochondria isolated from cerebral cortex and olfactory bulb of the rat.

The metabolic properties of mitochondria from rat cerebral cortex and olfactory bulb were investigated. The pyruvate-supported oxygen uptake rates by olfactory bulb mitochondria were significantly lower than those by cerebrocortical mitochondria. This is consistent with the differences in pyruvate dehydrogenase complex activities between these mitochondrial preparations. Pyruvate dehydrogenase kinase, NAD-linked isocitrate dehydrogenase, and hexokinase activities in olfactory bulb mitochondria were significantly lower than those in cerebrocortical mitochondria. However, NADP-linked isocitrate dehydrogenase, and NAD-linked and NADP-linked glutamate dehydrogenase activities in olfactory bulb mitochondria were significantly higher than those in cerebrocortical mitochondria. The differences between these two mitochondrial preparations in terms of the activities of these energy-metabolizing enzymes reflect the differences detected in the homogenates of these regions.

Animals↗

PubMed1985

Differences in the responses of brain cytosolic and mitochondrial hexokinases to three essential divalent metal ions.

Rat brain cytosolic and mitochondrial hexokinase activities were undetectable without added divalent cations. Mg2+ activated cytosolic (K0.5 of Mg2+ = 343 +/- 13 microM) and mitochondrial (K0.5 of Mg2+ = 183 +/- 8 microM) hexokinase in a concentration-related manner. The corresponding values for Mn2+ were 702 +/- 99 and 413 +/- 21 microM respectively. Ca2+, however, activated both forms of hexokinase poorly. In the presence of Mg2+, both Mn2+ and Cu2+ were more potent inhibitors of cytosolic hexokinase than mitochondrial hexokinase, whereas the inhibition of Cd2+ and Ca2+ did not show such selectivity. These results demonstrate that brain mitochondrial and cytosolic hexokinases differ significantly in their responses to divalent cations.

Animals↗

PubMed1985

Differential effects of monovalent, divalent and trivalent metal ions on rat brain hexokinase.

The effects of monovalent (Li+, Cs+) divalent (Cu2+, Ca2+, Sr2+, Ba2+, Zn2+, Cd2+, Hg2+, Pb2+, Mn2+, Fe2+, Co2+, Ni2+) and trivalent (Cr3+, Fe3+, Al3+) metals ions on hexokinase activity in rat brain cytosol were compared at 500 microM. The rank order of their potency as inhibitors of brain hexokinase was: Cr3+ (IC50 = 1.3 microM) greater than Hg2+ = Al3+ greater than Cu2+ greater than Pb2+ (IC50 = 80 microM) greater than Fe3+ (IC50 = 250 microM) greater than Cd2+ (IC50 = 540 microM) greater than Zn2+ (IC50 = 560 microM). However, at 500 microM Co2+ slightly stimulated brain hexokinase whereas the other metal ions were without effect. That inhibition of brain glucose metabolism may be an important mechanism in the neurotoxicity of metals is suggested.

Animals↗