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PubMed2002

Sensitization of singlet oxygen via encounter complexes and via exciplexes of pipi* triplet excited sensitizers and oxygen.

Both excited singlet states, 1sigma(g)+ and 1delta(g), and the triplet ground state, 3sigma(g)-, of molecular oxygen are competitively formed during the quenching by O2 of triplet (T1) excited sensitizers of sufficient energy. The corresponding overall rate constants kT(1sigma), kT(1delta), and kT(3sigma) as well as the T1 state energies E(T) and the oxidation potentials E(ox), have been determined for a series of six fluorene derivatives. Graduated and in part strong charge transfer (CT) effects on kT(1sigma), kT(1delta), and kT(3sigma) are observed. These and literature data strongly indicate that quenching occurs in two different channels each capable of producing O2(1sigma(g)-), O2(1delta(g)), and O2(3sigma(g)-). One proceeds via internal conversion (IC) of excited 1,3(T1 x 3sigma) complexes with no CT character (nCT), which cannot be distinguished from encounter complexes, the other via IC of 1,3(T1 x 3sigma) exciplexes with partial CT character (pCT). The contributions of nCT and pCT deactivation channels to the overall formation of O2(1sigma(g)+), O2(1delta(g)). and O2(3sigma(g)-) depend on E(T) and E(ox). The rate constants of the nCT channel are controlled by the excess energies of the respective IC processes by an energy gap law. The rate constants of the pCT channel depend on the change of free energy deltaG(CET) for complete electron transfer from T1 excited sensitizer to O2. Equations are presented which show the functional form of the dependence of the oxygen quenching rate constants on E(T) and E(ox). Particular emphasis is laid on the question of whether these relations could generally be valid for pipi* triplet sensitizers.

Journal Article↗
PubMed1981

Inhibition by adriamycin of calmodulin-sensitive and phospholipid-sensitive calcium-dependent phosphorylation of endogenous proteins from heart.

Adriamycin, a lipid-interacting anti-cancer agent, was found to inhibit phospholipid-sensitive Ca2+-dependent phosphorylation of endogenous proteins from the cytosol of the guinea-pig heart. The drug, unexpectedly, also inhibited phosphorylation of separate endogenous proteins in the cardiac cytosol and membranes catalysed by the calmodulin-sensitive species of Ca2+-dependent protein kinase. In both phosphorylation systems, the inhibition by adriamycin was reversed by either phospholipid (phosphatidylserine or cardiolipin) or calmodulin respectively. Adriamycin also inhibited phosphorylation of histone (exogenous protein) catalysed by purified cardiac phospholipid-sensitive Ca2+-dependent protein kinase, but not that by cyclic AMP-dependent and cyclic GMP-dependent protein kinases. It appears that Ca2+-dependent protein phosphorylation systems, regulated either by phospholipid or calmodulin, may represent hitherto unrecognized sites of action of adriamycin. It remains to be seen whether inhibition by adriamycin of these systems is related to the severe cardiotoxicity, the major adverse effect of the drug that limits its clinical usefulness.

Animals↗
PubMed1982

Inhibition by melittin of phospholipid-sensitive and calmodulin-sensitive Ca2+-dependent protein kinases.

Effects of melittin, an amphipathic polypeptide, on various species of protein kinases were investigated. It was found that melittin inhibited the newly identified phospholipid-sensitive Ca2+-dependent protein kinase (from heart, brain, spleen and neutrophils) and the cardiac myosin light-chain kinase, a calmodulin-sensitive Ca2+-dependent enzyme. In contrast, melittin had little or no effect on either the holoenzymes of the cardiac cyclic AMP-dependent and cyclic GMP-dependent protein kinases or the catalytic subunit of the former. Kinetic analysis indicated that melittin inhibited phospholipid-sensitive Ca2+-dependent protein kinase non-competitively with respect to ATP (Ki = 1.3 microM); although exhibiting complex kinetics, its inhibition of the enzyme was overcome by phosphatidylserine (a phospholipid cofactor), but not by protein substrate (histone H1) or Ca2+. On the other hand, melittin inhibited myosin light-chain kinase non-competitively with respect to ATP (Ki = 1.4 microM) or Ca2+ (Ki = 1.9 microM), and competitively with respect to calmodulin (Ki = 0.08 microM); although exhibiting complex kinetics, its inhibition of the enzyme was reversed by myosin light chains (substrate protein). The present findings indicate the presence of functionally important hydrophobic or hydrophilic loci on the Ca2+-dependent protein kinases, but not on the cyclic nucleotide-dependent class of protein kinase, with which melittin can interact. Moreover, the kinetic data suggest that melittin inhibited myosin light-chain kinase by interacting with a site on the enzyme the same as, or proximal to, the calmodulin-binding site, thus interfering with the formation of active enzyme-calmodulin-Ca2+ complex.

Adenosine Triphosphate↗
PubMed1995

Two classes of agonist-sensitive Ca2+ stores in platelets, as identified by their differential sensitivity to 2,5-di-(tert-butyl)-1,4-benzohydroquinone and thapsigargin.

In the absence of extracellular Ca2+, extensive Ca2+ release from the platelet intracellular stores [monitored as an increase of intracellular Ca2+ concentration ([Ca2+]i)] is produced by the combined action of the endomembrane Ca(2+)-ATPase inhibitor thapsigargin and 2 nM ionomycin. The titration of Ca2+ unloading with thapsigargin (plus ionomycin) shows that a substantial fraction of the store-associated Ca2+ is released by 8-10 nM thapsigargin, but that 100-200 nM thapsigargin is required for the complete release. The store depletion obtained in similar conditions with a different endomembrane Ca(2+)-ATPase inhibitor, 2,5-di-(tert-butyl)-1,4-benzohydroquinone (TBHQ), is always incomplete. It is completed by thrombin or by 10 nM thapsigargin. We conclude that two different types of Ca2+ pumps exist in platelets, one sensitive to TBHQ and to high thapsigargin, the other insensitive to TBHQ and sensitive to low thapsigargin. They are distributed separately in discrete subpopulations of the agonist-sensitive stores. The influx of external Ca2+ is maximal when both types of stores are Ca(2+)-depleted, either by high thapsigargin or by the combined action of low thapsigargin and TBHQ.

Antioxidants↗
PubMed1996

Thapsigargin activates univalent- and bivalent-cation entry in human neutrophils by a SK&F I3 96365- and Gd3+-sensitive pathway and is a partial secretagogue: involvement of pertussis-toxin-sensitive G-proteins and protein phosphatases 1/2A and 2B in the signal-transduction pathway.

The Ca2+-ATPase inhibitor thapsigargin (TG) activates bivalent-cation early in human neutrophils via depletion of intracellular Ca2+ stores bu little is known about the underlying mechanism and the functional role of TG-induced cation entry. We studied the effects of TG on univalent- and bivalent cation entry, lysozyme release and superoxide-anion (O2-) formation in human neutrophils. TG, like the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), stimulated entry of Ca2+, Mn2+, Ba2+, Sr2+ and Na+ in a 1-{beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride (SK&F 96365)- and Gd3+-sensitive manner. The inhibitors of protein phosphates 1/2A, calyculin A and okadaic acid, diminished TG-induced cation influxes, whereas the inhibitors of protein phosphatase 2B, cyclosporin A and FK-506, were potentiators. Pertussis toxin (PTX) partially inhibited the effects of TG on Ca2+ and Mn2+ entry. TG and fMLP activated inward currents with a linear current-voltage relationship and a reversal potential at about 0 mV. TG activated lysozyme release and potentiated fMLP-induced O2- formation. TG-induced lysozyme release was inhibited by SK&F 96365, PTX and the removal of extracellular Ca2+ or Na+. Our data show that TG activates a non-selective and SK&F 96365- and Gd3+-sensitive cation entry pathway and is a partial secretagogue. TG-stimulated cation entry involves PTX-sensitive G-proteins and protein phosphatases, with protein phosphatases 1/2A and 2B playing opposite roles.

Cations↗
PubMed2001

Insulin sensitivity decreases with obesity, and lean cats with low insulin sensitivity are at greatest risk of glucose intolerance with weight gain.

This study quantifies the effects of marked weight gain on glucose and insulin metabolism in 16 cats which increased their weight by an average of 44.2% over 10 months. Significantly, the development of feline obesity was accompanied by a 52% decrease in tissue sensitivity to insulin and diminished glucose effectiveness. In addition, glucose intolerance and abnormal insulin response occurred in some cats. An important finding was that normal weight cats with low insulin sensitivity and glucose effectiveness were at increased risk of developing impaired glucose tolerance with obesity. High basal insulin concentrations or low acute insulin response to glucose also independently increased the risk for developing impaired glucose tolerance. Male cats gained more weight relative to females and this, combined with their tendency to lower insulin sensitivity and higher insulin concentrations, may explain why male cats are at greater risk for diabetes. Results suggest an underlying predisposition for glucose intolerance in some cats, which is exacerbated by obesity. These cats may be more at risk of progressing to overt type 2 diabetes mellitus.

Animals↗
PubMed2001

Insulin sensitivity of blood glucose versus insulin sensitivity of blood free fatty acids in normal, obese, and obese-diabetic subjects.

We calculated insulin sensitivity indices (ISI) concerning the insulin effect on both glycemia and blood free fatty acids (FFA), named ISI(gly) and ISI(ffa), respectively, in 34 normal, 27 obese, and 11 obese-diabetic subjects by using the following formulas: ISI(gly)= 2/[(INSp x GLYp) +1], and ISI(ffa)= 2/[(INSp x FFAp)+1], in which INSp, GLYp, and FFAp = insulinemic, glycemic, and FFA areas during oral glucose tolerance test (OGTT) (75 g glucose, suggested sampling time: 0, 1, and 2 hours) of the person studied. A slight modification of these formulas allows the calculation of insulin resistance indices (IRI), ie, IRI(gly) and IRI(ffa). ISI and IRI are complementary, as their sum is always equal to 2, so that IRI can be deduced from ISI and vice versa. By using basal levels instead of areas, insulin sensitivity (or resistance) in the basal state can also be measured. Basal levels and areas are expressed by taking the mean normal value as 1, so that in normal subjects ISI(gly) and ISI(ffa), as well as IRI(gly) and IRI(ffa), are always around 1, with maximal variations comprised between 0 and 2. ISI(ffa) was markedly reduced in both the obese (mean, 0.47 +/- 0.04) and the obese-diabetic (mean, 0.41 +/- 0.06) subjects, whereas ISI(gly) was less reduced in the obese (mean, 0.57 +/- 0.04) than in the obese-diabetic (mean, 0.40 +/- 0.03) subjects. ISI(gly)-basal was less affected than ISI(ffa)-basal in both groups. Multiple regression showed that ISI(gly) and ISI(ffa) were significantly inversely correlated with age, body mass index (BMI), and diastolic (but not systolic) blood pressure. Meta-analysis of data from the literature showed that ISI(gly) was significantly correlated with the hyperinsulinemic-euglycemic clamp data. However, the "clamp" is performed under artificial, persistent hyperinsulinemia (which entails FFA suppression) as never occurs in the life of patients, whereas our indices are performed under physiologic conditions, and represent simple tools suitable for clinical or epidemiologic studies, allowing assessment of whole-body insulin sensitivity with regard to both glycemia and blood FFA.

Adult↗
PubMed2002

Aspirin-sensitive versus non-aspirin-sensitive nasal polyp patients: analysis of leukotrienes/Fas and Fas-ligand expression.

OBJECTIVE: The goal of the present study was to identify levels of leukotrienes released by leukocytes and nasal polyps from aspirin-sensitive patients (ASPs) and non-aspirin-sensitive patients (NASPs) after exposure to various concentrations of aspirin. Eosinophil expressions of apoptosis regulators were also compared. STUDY DESIGN AND SETTING: Leukotriene release from nasal polyps and leukocytes of ASPs and NASPs was measured after exposure to differing concentrations of aspirin. Eosinophils were analyzed for Fas and Fas ligand receptors using flow cytometry. RESULTS: NASPs showed increased leukotriene release from nasal polyps on increased aspirin exposure. Polyps from ASPs did not show any change. ASPs showed greater leukotriene release from blood on increasing aspirin exposure compared with NASPs. Flow cytometric analysis showed eosinophils in the peripheral blood of ASPs have decreased Fas expression compared with those of NASPs. CONCLUSIONS: This study showed differences in leukotriene release and eosinophil apoptosis between ASPs and NASPs. SIGNIFICANCE: These findings suggest a role of leukotrienes and eosinophils in aspirin sensitivity mechanisms in blood.

Adult↗
PubMed1974

Demonstration of dopamine-sensitive adenylate cyclase in malignant neuroblastoma cells and change in sensitivity of adenylate cyclase to catecholamines in "differentiated" cells.

Adenylate cyclase (EC 4.6.1.1) activity was stimulated by low concentrations of dopamine and apomorphine, but not by low concentrations of norepinephrine in homogenates of malignant mouse neuroblastoma cells. In cyclic AMP-induced "differentiated" cells, dopamine concentration required for a maximal increase in adenylate cyclase activity was about 10-fold less than that required for a similar increase in control cells, and norepinephrine-sensitive adenylate cyclase activity became apparent at low norepinephrine concentrations. The pharmacological properties of dopamine-sensitive adenylate cyclase were different from those of norepinephrine-sensitive enzyme. For example, dopamine-stimulated adenylate cyclase activity was markedly reduced by low concentrations of haloperidol and phentolamine, whereas norepinephrine-stimulated enzyme activity required higher concentrations of these blocking agents for a similar amount of inhibition. Norepinephrine-stimulated enzyme activity was markedly blocked by low concentrations of propranolol, whereas dopamine-stimulated enzyme activity required a much higher concentration of this blocking agent for a similar amount of inhibition. Low concentrations of isoproterenol increased adenylate cyclase activity in malignant cells, but in "differentiated" cells even a high concentration failed to do so. The fact that dopamine and norepinephrine produced an additive stimulatory effect on adenylate cyclase activity suggests that they interact at different receptor sites. This suggestion is further supported by the observation that the combination of prostaglandin E(1) and norepinephrine produced an additive stimulatory effect of enzyme activity. The observation that the effects of dopamine and prostaglandin E(1) are not additive, coupled with the observation that a low concentration of phentolamine blocked the effect of prostaglandin E(1), suggests that these two agents may interact at a common site.

Adenylyl Cyclases↗
PubMed1999

Alternative splicing of sur2 Exon 17 regulates nucleotide sensitivity of the ATP-sensitive potassium channel.

ATP-sensitive potassium channels (KATP) are implicated in a diverse array of physiological functions. Previous work has shown that alternative usage of exons 14, 39, and 40 of the muscle-specific KATP channel regulatory subunit, sur2, occurs in tissue-specific patterns. Here, we show that exon 17 of the first nucleotide binding fold of sur2 is also alternatively spliced. RNase protection demonstrates that SUR2(Delta17) predominates in skeletal muscle and gut and is also expressed in bladder, fat, heart, lung, liver, and kidney. Polymerase chain reaction and restriction digest analysis of sur2 cDNA demonstrate the existence of at least five sur2 splice variants as follows: SUR2(39), SUR2(40), SUR2(Delta17/39), SUR2(Delta17/40), and SUR2(Delta14/39). Electrophysiological recordings of excised, inside-out patches from COS cells cotransfected with Kir6.2 and the sur2 variants demonstrated that exon 17 splicing alters KATP sensitivity to ATP block by 2-fold from approximately 40 to approximately 90 microM for exon 17 and Delta17, respectively. Single channel kinetic analysis of SUR2(39) and SUR2(Delta17/39) demonstrated that both exhibited characteristic KATP kinetics but that SUR2(Delta17/39) exhibited longer mean burst durations and shorter mean interburst dwell times. In sum, alternative splicing of sur2 enhances the observed diversity of KATP and may contribute to tissue-specific modulation of ATP sensitivity.

ATP-Binding Cassette Transporters↗
PubMed2001

Dynamic sensitivity of ATP-sensitive K(+) channels to ATP.

ATP and MgADP regulate K(ATP) channel activity and hence potentially couple cellular metabolism to membrane electrical activity in various cell types. Using recombinant K(ATP) channels that lack sensitivity to MgADP, expressed in COSm6 cells, we demonstrate that similar on-cell activity can be observed with widely varying apparent submembrane [ATP] ([ATP](sub)). Metabolic inhibition leads to a biphasic change in the channel activity; activity first increases, presumably in response to a fast decrease in [ATP](sub), and then declines. The secondary decrease in channel activity reflects a marked increase in ATP sensitivity and is correlated with a fall in polyphosphoinositides (PPIs), including phosphatidylinositol 4,5-bisphosphate, probed using equilibrium labeling of cells with [(3)H]myo-inositol. Both ATP sensitivity and PPIs rapidly recover following removal of metabolic inhibition, and in both cases recovery is blocked by wortmannin. These data are consistent with metabolism having a dual effect on K(ATP) channel activity: rapid activation of channels because of relief of ATP inhibition and much slower reduction of channel activity mediated by a fall in PPIs. These two mechanisms constitute a feedback system that will tend to render K(ATP) channel activity transiently responsive to a change in [ATP](sub) over a wide range of steady state concentrations.

Adenosine Diphosphate↗
PubMed2003

Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact.

Lipid metabolism plays an important role in glucose homeostasis under normal and pathological conditions. In adipocytes, skeletal muscle, and pancreatic beta-cells, lipids are mobilized from acylglycerides by the hormone-sensitive lipase (HSL). Here, the consequences of a targeted disruption of the HSL gene for glucose homeostasis were examined. HSL null mice were slightly hyperglycemic in the fasted, but not fed state, which was accompanied by moderate hyperinsulinemia. During glucose challenges, however, disposal of the sugar was not affected in HSL null mice, presumably because of release of increased amounts of insulin. Impaired insulin sensitivity was further indicated by retarded glucose disposal during an insulin tolerance test. A euglycemic hyperinsulinemic clamp revealed that hepatic glucose production was insufficiently blocked by insulin in HSL null mice. In vitro, insulin-stimulated glucose uptake into soleus muscle, and lipogenesis in adipocytes were moderately reduced, suggesting additional sites of insulin resistance. Morphometric analysis of pancreatic islets revealed a doubling of beta-cell mass in HSL null mice, which is consistent with an adaptation to insulin resistance. Insulin secretion in vitro, examined by perifusion of isolated islets, was not impacted by HSL deficiency. Thus, HSL deficiency results in a moderate impairment of insulin sensitivity in multiple target tissues of the hormone but is compensated by hyperinsulinemia.

Adipocytes↗
PubMed1962

A transient stage of suspected delayed sensitivity during the early induction phase of immediate corneal sensitivity.

1. If quantities of bovine serum albumin or bovine gamma globulin in the range of 2 to 4 mg are inoculated intracorneally into rabbits, a biphasic reaction occurs in the cornea. 2. The primary reaction, which becomes manifest approximately 3 days after inoculation and lasts several days, is characterized by a diffuse clouding of the cornea. During this period, no antibody can be demonstrated either by serological or histological techniques. The animals react with a delayed type of skin reaction and the sensitivity can be passively transferred to normal guinea pigs with the cells of pooled lymph nodes or buffy coats. The corneal reaction is therefore considered a manifestation of delayed sensitivity. 3. The secondary reaction in the cornea, usually occurring about the 14th day after inoculation is the "Wessely phenomenon." This reaction is characterized by a precipitation of immune complexes in the cornea resulting in a visible annular corneal opacity. Circulating antibody can be readily demonstrated by both serological and histological techniques and the animals demonstrate typical Arthus skin sensitivity. 4. Generally intervening between these two phases of corneal activity is a stage in which the inoculated eye appears essentially normal. This stage is eliminated if both corneas are inoculated initially.

Animals↗
PubMed1964

THE SEDIMENTATION PROPERTIES OF THE SKIN-SENSITIZING ANTIBODIES OF RAGWEED-SENSITIVE PATIENTS.

The sedimentation coefficients of the skin-sensitizing antibodies to ragweed were evaluated by the moving partition cell method and the sucrose density gradient method. The most reliable results were obtained by sucrose density gradient ultracentrifugation which showed that the major portion of skin-sensitizing antibodies to ragweed sediment with an average value of 7.7S (7.4 to 7.9S). This is about one S unit faster than gamma-globulins (6.8S). The data from the moving partition cell method are in agreement with these results. Our studies failed to demonstrate heterogeneity of the skin-sensitizing antibodies with regard to sedimentation rate.

Ambrosia↗
PubMed1965

The bacterial induction of homograft sensitivity. I. Effects of sensitization with group A streptococci.

Heat-killed Group A hemolytic streptococci can induce in guinea pigs a state of altered reactivity to skin homografts which is indistinguishable from that which results from sensitization with homologous tissues. Challenge of suitably prepared recipients with first-set skin homografts obtained from unrelated randomly selected donors elicits white graft reactions or accelerated rejection of such grafts. The gross and histologic appearance of these grafts is identical with that observed in similar reactions obtained in guinea pigs sensitized with homologous tissues. The ability of Group A hemolytic streptococci to induce homograft sensitivity in the guinea pig is a property shared by Types 4, 5, 6, 11, 12, 14, and 49 of Group A streptococci.

Animals↗
PubMed1981

Contact sensitivity to azobenzenearsonate and its inhibition after interaction of sensitized cells with antigen-conjugated cells.

Painting mice on the skin with the diazonium salt of p-arsanilic acid elicited two types of T cell activity. One was restricted by the I region of the major histocompatibility complex and was responsible for the transfer of azobenzenearsonate (ABA) sensitivity to naive mice. The other was H-2K restricted and could be demonstrated by its ability to interact specifically with ABA-coupled cells in vitro and to inhibit nonspecifically the transfer of sensitivity by cells sensitized either to ABA or to another antigen. Free antigen, or antibody directed against the cross-reactive idiotype on the anti-ABA antibodies of A/J mice, could inhibit the H-2K-restricted suppressive activity induced in the ABA immune A/J cells.

Animals↗
PubMed1997

Molecular bases of three characteristic phenotypes of pneumococcus: optochin-sensitivity, coumarin-sensitivity, and quinolone-resistance.

Streptococcus pneumoniae is uniquely sensitive to amino alcohol antimalarials in the erythro configuration, such as optochin, quinine, and quinidine. The protein responsible for the optochin (quinine)-sensitive (Opts, Qins) phenotype of pneumococcus is the proteolipid c subunit of the FzeroF1 H(+)-ATPase. OptR/QinR isolates arose by point mutations in the atpC gene and produce different amino acid changes in one of the two transmembrane alpha-helices of the c subunit. In addition, comparison of the sequence of the atpCAB genes of S. pneumoniae R6 (Opts) and M222 (an OptR strain produced by interspecies recombination between pneumococcus and S. oralis), and S. oralis (OptR) revealed that, in M222, an interchange of atpC and atpA had occurred. We also demonstrate that optochin, quinine, and related compounds specifically inhibited the membrane-bound ATPase activity. Equivalent differences between Opts/Qins and OptR/QinR strains, both in growth inhibition and in membrane ATPase resistance, were found. Pneumococci also show a characteristic sensitivity to coumarin drugs, and a relatively high level of resistance to most quinolones. We have cloned and sequenced the gyrB gene, and characterized novobiocin resistant mutants. The same amino acid substitution (Ser-127 to Leu) confers novobiocin resistance on four isolates. This residue position is equivalent to Val-120 of Escherichia coli ryGB, a residue that lies inside the ATP-binding domain but is not involved in novobiocin binding in E. coli, as revealed by crystallographic data. In addition, the genes encoding the ParC and ParE subunits of topoisomerase IV, together with the region encoding amino acids 46 to 172 (residue numbers as in E. coli) of the pneumococcal ryGA subunit, were characterized in respect to fluoroquinolone resistance. The gyrA gene maps to a physical location distant from the gyrB and parEC loci on the chromosome. Ciprofloxacin-resistant (CpR) clinical isolates had mutations affecting amino acid residues of the quinolone resistance-determining region of ParC (low-level CpR), or in both resistance-determining regions of ParC and GyrA (high-level CpR). Mutations were found in residue positions equivalent to Ser-83 and Asp-87 of the E. coli GyrA subunit. Transformation experiments demonstrated that topoisomerase IV is the primary target of ciprofloxacin, DNA gyrase being a secondary one.

Amino Acid Sequence↗
PubMed1987

The sizes of cellular deoxynucleoside 5'-triphosphate pools in relation to sensitivity to electron irradiation using sensitive and resistant cell lines.

The deoxynucleoside 5'-triphosphate (dNTP) pool sizes have been determined before and after electron (e-) irradiation in sets of radiation sensitive and resistant cell lines. In the L5178Y mouse lymphoma radiosensitive line (LS), the dTTP pool fell 50% following irradiation, whilst the three other dNTP pools remained unaltered. On the other hand, for the radioresistant line (AII) all four dNTP pools increased by 2-to 3-fold. The dNTP pools of the Chinese hamster radiosensitive (V79) line and radioresistant (V79/79) lines were unaltered by the radiation, but a difference in pool size was present before irradiation, with the pools of the V79 cells being approximately twice those of the V79/79 cells. Two out of the three ataxia telangiectasia cell lines studied show reduced dNTP pools when compared with those of normal human fibroblasts and these pools were also unaltered by the radiation. In the L5178Y and Chinese hamster cells the levels of enzymes involved in the biosynthesis of dNTPs have been determined. In general the higher the level of ribonucleoside diphosphate reductase (RDR) the larger the cellular pools. The observed levels of RDR could, in part, explain the observed results. Increasing the dTTP pool by the addition of deoxythymidine and deoxycytidine to the cell culture with the V79/79 cells reduced their sensitivity to the radiation. These results indicate a relationship between a cell's sensitivity to e- irradiation and the sizes of the cellular dNTP pools. However, the exact nature of any such relationship is unknown.

Animals↗