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T F Slater

Publications and source records attributed to T F Slater.

At least 19 recordsLinked to original sources
PubMed1994

Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: an HPLC and ESR study.

Previous studies examining the involvement of oxidative stress in the substantia nigra in Parkinson's disease have measured terminal products of lipid peroxidation or the function of antioxidant defense systems. We report a more specific early marker of lipid peroxidation, lipid hydroperoxides, in a high-performance liquid chromatography (HPLC) and electron spin resonance (ESR) investigation. HPLC-chemiluminescent detection revealed two classes of lipid hydroperoxides in brain tissue extracts--free fatty acid hydroperoxides and cholesterol lipid hydroperoxides. Only cholesterol lipid hydroperoxides were consistently detected in all tissue extracts. Cholesterol lipid hydroperoxides had a 10-fold increase in the Parkinson's disease substantia nigra compared to control subjects. ESR detection of radical degradation products, including those of lipid hydroperoxides, in nigral homogenates incubated with the spin trap N-t-butyl-alpha-phenyl nitrone (PBN) showed a marked variation in ESR signal between tissues. Despite the increased levels of lipid hydroperoxides in parkinsonian substantia nigra, there was no overall difference in ESR signal intensity between nigral tissues from controls and from patients with Parkinson's disease. The increased levels of an early component of the peroxidation chain in substantia nigra in Parkinson's disease support the hypothesis of a continuous toxic process involving oxygen radical activity. However, using previously frozen tissue, ESR evidence for increased radical formation could not be demonstrated.

Chromatography, High Pressure Liquid↗
PubMed1994

Direct relationship between ischaemic burden and myocardial release of products of lipid peroxidation in patients undergoing percutaneous transluminal coronary angioplasty.

BACKGROUND: Recent studies have shown that free radical activity is increased in humans during percutaneous transluminal coronary angioplasty. These studies, however, have failed to localize the site of free radical activity or to demonstrate a relationship between ischaemic burden and free radical production. METHODS: The relationship between ischaemic burden and subsequent lipid peroxidation was studied during 16 inflations in eight patients undergoing angioplasty to anterior descending artery lesions. Two inflations 15 min apart were studied in each patient, one using a conventional (occlusive) balloon and one using the ACS Rx 'perfusion' balloon. The severity of the ischaemic insult associated with each inflation was assessed by contrast ventriculography, change in left ventricular end-diastolic pressure and myocardial lactate release 30 s after balloon deflation. Plasma levels of lipid peroxidation products were assessed by analysis of thiobarbituric-acid-reactive substances. RESULTS: A direct relationship was observed between the ischaemic burden and the myocardial release of lipid peroxidation products over the first 4 min after balloon deflation (F = 5.6; P < 0.006). In each patient, one of the inflations was associated with a greater degree of ischaemia. Left ventricular ejection fraction was lower (P < 0.001) and left ventricular end-diastolic pressure was higher (P < 0.002) during the 'ischaemic' inflations. Myocardial release of lipid peroxidation products was significantly higher after the 'ischaemic' balloon inflation (F = 7.65; P < 0.009). CONCLUSION: Brief periods of human myocardial ischaemia result in myocardial release of lipid peroxidation products in direct proportion to the severity of the preceding ischaemic insult.

Aged↗
PubMed1994

Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxidation in patients undergoing coronary artery bypass grafting.

In this prospective, randomized, double-blind, placebo-controlled study, the clinical, biochemical, and hemodynamic effects of xanthine oxidase inhibition in patients undergoing coronary artery bypass grafting were assessed. Allopurinol pretreatment significantly reduced the use of inotropic support after the operation (5 of 25 patients versus 13 of 25 patients, p < 0.01) and increased the rate of peripheral warming (11.4 +/- 0.85 hours versus 14.4 +/- 1 hours, p < 0.02). Twenty patients (9 in the allopurinol group and 11 in the placebo group) underwent invasive hemodynamic monitoring and intraoperative coronary sinus cannulation. The cardiac indexes of both groups were similar before the operation and for the first postoperative hour; thereafter, the cardiac index increased significantly in only the active treatment group (F = 3.33 and df = 5.90, p < 0.004). Products of lipid peroxidation (thiobarbituric acid reactive substances) increased significantly in only the placebo group, with increases being evident both in the systemic circulation (9.5 +/- 3.2 nmol/gm albumin, p < 0.007, and 24 +/- 5 nmol/gm albumin, p < 0.001, at 30 seconds and 2 minutes of reperfusion, respectively) and the coronary sinus (19.4 +/- 5.8 nmol/gm albumin, p < 0.004, and 28 +/- 4 nmol/gm albumin, p < 0.001, at 2 and 5 minutes of reperfusion, respectively. No significant difference was evident between the groups with respect to cardiac enzyme or vitamin E release. It is proposed that xanthine oxidase inhibition exerts its beneficial effects by reducing the level of free radical activity associated with reperfusion during coronary artery bypass grafting.

Adult↗
PubMed1993

Constitutive and inducible profile of glutathione S-transferase subunits in biliary epithelial cells and hepatocytes isolated from rat liver.

The constitutive and inducible cytosolic glutathione S-transferase (EC 2.5.1.18) subunit compositions of parenchymal cells (hepatocytes) and biliary epithelial cells (BEC) from rat liver have been quantitatively analysed using reverse-phase h.p.l.c. Hepatocytes, analysed in the absence of non-parenchymal cells, expressed constitutively the following subunits, in order of their concentration: 3, 4, 2, 1a, 1b, 8, 6 and 10. BEC express constitutively only four of the GST subunits expressed by hepatocytes and these are, in order of their concentration: subunits 2, 7, 4 and 3. Notable differences from hepatocytes are that BEC completely lack the Alpha-class subunits 1a and 1b that are major subunits in hepatocytes, Mu-class subunits make up a very low proportion of the total, and the Pi-class subunit 7 is a major subunit in BEC, whereas it is essentially absent from hepatocytes. For the first time, the effects of the inducing agents phenobarbitone (PB), beta-naphthoflavone (beta-NF) and ethoxyquin (EQ) have been characterized in a comprehensive and quantitative manner in both cell types. PB, beta-NF and EQ increased total GST protein in hepatocytes by approx. 2-fold, 3-fold and 4-fold respectively. Subunits significantly induced in hepatocytes were (in order of fold-induction): by PB, 1b > 8 > 3 > 2 > 4; by beta-NF, 1b > 8 > 2 > 3 > 4; and by EQ, 7 > 1b > 10 > 8 > 3 > 2 > 1a > 4. In BEC, neither PB nor beta-NF had significant effects on the total amount of GST protein, although PB did significantly induce subunit 3 at the expense of other subunits. EQ increased total GST protein nearly 5-fold in BEC, subunits 7 and 3 being induced dramatically above constitutive levels.

Animals↗
PubMed1993

Measurement of n-alkanals and hydroxyalkenals in biological samples.

A modified method was developed to measure nM levels of a range of n-alkanals and hydroxyalkenals in biological samples such as blood plasma and tissue homogenates and also in Folch lipid extracts of these samples. Butylated hydroxytoluene (BHT) and desferrioxamine (Desferal) were added to samples to prevent artifactual peroxidation. Aldehydes were reacted with 1,3-cyclohexanedione (CHD), cleaned up by solid-phase extraction on a Sep-Pak C18 cartridge and the fluorescent decahydroacridine derivatives resolved by reverse-phase high-performance liquid chromatography (HPLC) with gradient elution. A wider range of aldehydes was detected in lipid extracts of plasma and liver homogenate compared to whole (unextracted) samples. Human plasma contained nM levels of acetaldehyde, propanal, butanal, pentanal, hexanal, and heptanal. 4-Hydroxynonenal (0.93 nmol/g) and alkanals with two to six carbons (up to 7.36 nmol/g) were detected in rat liver. Recovery of aldehydes added to whole plasma or to lipid extracts of plasma was dependent on carbon chain length, varying from 95% for acetaldehyde to 8% for decanal. Recovery from biological samples was significantly less than that of standards taken through the Sep-Pak clean-up procedure, suggesting that aldehydes can bind to plasma protein and lipid components.

Aldehydes↗
PubMed1993

An introduction to free radical biochemistry.

Free radicals are chemical species possessing an unpaired electron that can be considered as fragments of molecules and which are generally very reactive. They are produced continuously in cells either as accidental by-products of metabolism or deliberately during, for example, phagocytosis. The most important reactants in free radical biochemistry in aerobic cells are oxygen and its radical derivatives (superoxide and hydroxyl radical), hydrogen peroxide and transition metals. Cells have developed a comprehensive array of antioxidant defences to prevent free radical formation or limit their damaging effects. These include enzymes to decompose peroxides, proteins to sequester transition metals and a range of compounds to 'scavenge' free radicals. Reactive free radicals formed within cells can oxidise biomolecules and lead to cell death and tissue injury. Establishing the involvement of free radicals in the pathogenesis of a disease is extremely difficult due to the short lifetimes of these species.

Animals↗
PubMed1993

Lipid peroxidation and changes in vitamin E levels during coronary artery bypass grafting.

The effects of ischemia and reperfusion on arterial and coronary sinus vitamin E and thiobarbituric acid reactive substance levels were investigated in 10 patients undergoing routine coronary artery bypass grafting. Serial sampling was performed during bypass operations, before the initial period of crossclamping and at 30 seconds and 2, 5, and 10 minutes after final crossclamp removal. A net myocardial loss of vitamin E occurred in the first 5 minutes of myocardial reperfusion (0.84 +/- 0.21 mumol/mmol cholesterol; p < 0.01). Myocardial vitamin E loss correlated positively with the total crossclamp time (rho = -0.695; p < 0.05) but was independent of cardiac enzyme release and duration of cardiopulmonary bypass. The concentration of thiobarbituric acid reactive substance rose significantly in the systemic circulation (+14 nmol/gm albumin; F > 17; p < 0.002) at 2 and 5 minutes after crossclamp removal. A significant increase of thiobarbituric acid reactive substance levels was also found in the coronary sinus blood 10 minutes after crossclamp removal (+8 nmol/gm albumin; F > 14; p < 0.004). However, there was no net arterial-coronary sinus difference in thiobarbituric acid reactive substance levels. The change in arterial thiobarbituric acid reactive substance levels in each patient was inversely correlated with their control vitamin E level (F = 9.53; p < 0.01). Our findings suggest that systemic lipid peroxidation occurs during bypass and that vitamin E may play a protective role during routine bypass grafting by attenuating the degree of peroxidative damage.

Angina Pectoris↗
PubMed1992

Increased activity of 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase in purified cell suspensions and single cells from the uterine cervix in cervical intraepithelial neoplasia.

The activities of 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase have been measured in squamous epithelial cells of the uterine cervix from normal patients and cases of cervical intraepithelial neoplasia (CIN). A biochemical cycling method, which uses only simple equipment and is suited to routine use and to automation, was applied to cells separated by gradient centrifugation. In addition, cells were examined cytochemically, and the intensity of staining in the cytoplasm of single whole cells was measured using computerised microcytospectrophotometry. Twenty per cent of cells in samples from normal patients (n=61) showed staining intensities above an extinction of 0.15 at 540 nm, compared to 71% of cases of CIN 1 (n=14), 91% of cases of CIN 2 (n=11) and 67% of cases of CIN 3 (n=15). The cytochemical data do not allow definitive distinctions to be made between different grades of CIN whereas the biochemical assay applied to cell lysates shows convincing differences between normal samples and cases of CIN. There are no false negatives for CIN 3 (n=14) and CIN 2 (n=10) and 11% false negatives for CIN 1 (n=9) and 14% of false positives for normal cases (n=21). The results of this preliminary study with reference to automation are discussed [corrected].

Cell Separation↗
PubMed1991

Exposure of beta L-crystallin to oxidizing free radicals enhances its susceptibility to transglutaminase activity.

1. The effects of free radicals on the capacity of beta L-crystallin to act as a substrate for the enzyme transglutaminase were investigated. 2. beta L-Crystallin was exposed to defined radical species that were generated radiolytically, and transglutaminase activity, using the modified protein as substrate, was subsequently measured by monitoring the incorporation of [14C]putrescine. 3. Exposure of beta L-crystallin to hydroxyl radicals, thymine peroxyl radicals and acetone peroxyl radicals at concentrations of up to 135 microM increased the capacity of the protein to incorporate putrescine. With higher concentrations of these radicals this capacity of beta L-crystallin to act as a transglutaminase substrate declined to control levels or lower. 4. Superoxide radicals were inactive in this regard; hydroperoxyl radicals were active only at high concentrations. 5. It has previously been suggested that changes in the crystallins that occur during aging and with cataract may be due to oxidative reactions and to transglutaminase activity. This study suggests that these phenomena may be considered together rather than separately.

Animals↗
PubMed1991

Cellular thiols in rat liver cell lines possessing different growth characteristics.

Thiol levels were measured in three cell lines derived from rat hepatocytes with different growth rates and degrees of tumorigenicity: IAR20 having normal epithelial morphology and no tumour forming ability; IAR6.1 being a chemically-transformed malignant cell line; and IAR6.1RT7 derived from an epithelial tumour obtained after injection of IAR6.1 cells into a syngenic animal. The mean levels of GSH, GSSG, low molecular weight thiols (LMWT), macromolecular thiols (MT) and total reactive protein sulphur (TRPS), expressed as nmoles-SH mg-1 protein, were found to be 25.5, 7.5, 50.1, 114.5 and 143.6 respectively for IAR20; 37.6, 3.9, 65.4, 126.8 and 148.4 for IAR6.1; 17.2, 4.4, 52.3, 141.0 and 168.2 for IAR6.1RT7. Cultures were treated with D,L-buthionine-S,R-sulphoximine (BSO) to cause greater than 70 per cent depletion of GSH and the measurements of cellular thiols repeated. Although treatment with BSO caused a substantive decrease in the LMWT fraction, there were no major changes in macromolecular thiols or in total reactive protein sulphur. The respective mean values for LMWT, MT and TRPS (expressed as nmoles-SH mg-1 protein) were 19.4, 109.8, 136.3 for IAR20; 17.2, 119.3, 143.6 for IAR6.1; 21.6, 150.7 and 163.5 for IAR6.1RT7. It is concluded that significant differences in thiol levels exist between the three rat liver cell lines studied. However, severe acute depletion of GSH is not reflected by changes in the levels of macromolecular thiols which suggests that there is only a slow equilibrium between these two major thiol pools.

Animals↗
PubMed1991

Measurement of lipid hydroperoxides in normal human blood plasma using HPLC-chemiluminescence linked to a diode array detector for measuring conjugated dienes.

A modification of a method using high-performance liquid chromatography (HPLC) with chemiluminescence (CL) detection for the measurement of lipid hydroperoxides (LOOH) in human blood plasma has been developed. The system involves separation of different classes of LOOH using reverse-phase HPLC, and post-column detection of CL produced by isoluminol oxidation during the reaction of LOOH with microperoxidase. Complete ultra-violet absorption spectra are collected with an in-line diode-array detector and used to confirm a positive CL response due to LOOH, or other compounds, by the presence or absence, respectively, of the LOOH conjugated diene chromophore. We have used the method to investigate the stability of exogenous 15(S)-HPETE (a hydroperoxide of eicosatetraenoic acid) and conjugated dienes (of both 15(S)-HPETE and its reduced metabolite, 15(S)-HETE) in human plasma stored at various temperatures. A large and rapid loss of the hydroperoxide occurred in plasma incubated at 0 degrees C or 27 degrees C, whereas only a small reduction in the level of conjugated dienes was found. 15(S)-HPETE in PBS was stable under the same conditions, and zero time recovery of the hydroperoxide from denatured plasma and from buffer containing albumin was identical to that of fresh plasma. Our data suggest that the observed temperature-dependent loss of exogenous hydroperoxide from fresh plasma results from a combination of enzymatic degradation to the hydroxy derivative and binding to plasma albumin. 15(S)-HPETE was found to be stable in plasma stored at -70 degrees C for up to 2 weeks and in liquid nitrogen for 3 months in the presence of the antioxidants butylated hydroxytoluene (BHT) and desferal, with no significant loss of conjugated dienes.

Antioxidants↗
PubMed1991

The reactivity of the SH group of bovine serum albumin with free radicals.

The reactivity of the SH group of bovine serum albumin (BSA) towards free radicals generated by several different systems including gamma-radiolysis and hydrogen peroxide/metal salt mixtures was investigated. On exposure of BSA (1 mg/ml and 5 mg/ml) to HO. radicals generated radiolytically the protein-SH concentration was found to decrease in a dose-dependent manner. At 40 mg/ml albumin no loss of SH was observed. O2-. and HO2. radicals were much less aggressive towards the SH group. The effect of divalent metal salts (copper or iron) plus hydrogen peroxide was studied separately and in combination. H2O2 alone caused a decrease in SH group concentration the rate of which was not decreased by the presence of desferrioxamine and so was apparently not due to reactions catalysed by adventitious metal ions. Copper alone caused a dose-dependent decrease in SH group concentration and the mixture of the two agents caused a greater loss of SH than each separate component. However, this latter effect was again resistant to the effects of desferrioxamine. The SH group of BSA was only moderately sensitive to the presence of ferrous iron alone and in a system containing both ferrous iron and H2O2 rates of SH oxidation were obtained that were identical to those obtained with H2O2 alone. Desferrioxamine again did not alter the rate of SH oxidation in these experiments. We suggest that the highly reactive free radical HO. is not able to reach and to oxidize the SH group of BSA when generated by metal/H2O2 mixtures, in contrast to HO. generated radiolytically. Less reactive radicals and non-radical species such as H2O2 have more potential for doing so.

Cations, Divalent↗
PubMed1991

Detection of free radicals and cholesterol hydroperoxides in blood taken from the coronary sinus of man during percutaneous transluminal coronary angioplasty.

Patients undergoing percutaneous transluminal coronary angioplasty (PTCA) were investigated for the production of free radicals and cholesterol hydroperoxides during reperfusion. Fifteen patients were studied. Ischaemia during balloon inflation was assessed by serial coronary sinus lactate analysis (mean maximal increase in anterior descending artery dilation was 130%), and by the demonstration of reperfusion hyperaemia (mean increase of coronary sinus oxygen saturation 74%). Free radicals were detected by electron spin resonance (ESR) spin trapping using the spin trap PBN (N-t-Butyl-alpha-phenylnitrone). Radical adducts were detected in up to 50% of samples taken during reperfusion after anterior descending lesion angioplasty. No radicals were detected in control samples or during the ischaemic phase. Radical detection was positively correlated with the change in coronary sinus lactate (p less than 0.025). Coronary sinus cholesterol hydroperoxide analysis did not show a significant increase over control during reperfusion, due in part to unexpectedly high pre angioplasty levels. This study provides clear evidence for the production of a burst of free radicals and evidence for lipid peroxidation in the minutes following myocardial reperfusion during angioplasty. A relationship between the severity of the ischaemic insult and the detection of radical adducts has also been found.

Angina Pectoris↗
PubMed1990

Quantitative measurements of the changes in protein thiols in cervical intraepithelial neoplasia and in carcinoma of the human uterine cervix provide evidence for the existence of a biochemical field effect.

Quantitative micromethods have been used for measuring reactive protein thiols (PSHr), total reactive protein sulfur (TRPS), total protein thiols (PSHt), and protein disulfides (PDS) in fixed frozen sections of human uterine cervix. PSHr and TRPS were stained using 2,2'-dihydroxy-6,6'-dinaphthyl disulfide; PSHt and PDS were stained using mercurochrome methods. Microspectrophotometric measurements were made on the stained sections using a microdensitometer with associated data processing; the results obtained for areas of epithelium and stroma were converted to absorbance values per micron 2. Samples of uterine cervix that were diagnosed as containing cervical intraepithelial neoplasia (CIN) I-III or carcinoma were examined and compared with samples of normal uterine cervix. Measurements were made not only on identified lesions but also on apparently normal tissue obtained from the same cervix. Epithelial/stroma ratios (E/S) were calculated for PSHr, TRPS, PSHt and PSHt + PDS; in addition, the double ratios of PSHr/TRPS and PSHt/PSHt + PDS were also calculated for E/S. The mean E/S values for PSHr and PSHt were significantly different for all types of lesion compared with control samples. The E/S ratios for apparently normal tissue obtained from cervices with CIN or carcinoma were also significantly different compared with corresponding control values, indicating a field effect. There was a considerable degree of overlap between individual values in the control groups versus those obtained with each type of lesion. The corresponding mean E/S values for TRPS and for PSHt + PDS in the samples containing lesions were not significantly different from control means except for the group containing CaCx. However, the mean values for the double ratios (PSHr/TRPS and PSHt/PSHt + PDS) were significantly different in the groups containing lesions compared with the controls. Moreover, apparently normal tissue obtained from cervices containing CIN or carcinoma had different mean values compared with the controls, confirming the existence of a field effect. The degree of overlap of individual values in the lesion groups compared with the control values was much less with double ratio values than previously noted for single ratio values. In consequence, the double ratio measurements clearly discriminated CIN I + II and CIN-III from controls. Our data show that CIN is associated with marked changes in tissue protein thiols and disulfides and that these differences extend to neighboring apparently normal tissue indicative of a field effect.

Adult↗
PubMed1990

Menadione and cumene hydroperoxide induced cytotoxicity in biliary epithelial cells isolated from rat liver.

Biliary epithelial cells (BEC) and parenchymal cells isolated from normal rat liver were exposed in vitro to a number of toxic compounds. BEC were found to be highly sensitive to concentrations of menadione (100 microM) and cumene hydroperoxide (10 microM) that are usually not effective as toxic agents in hepatocytes under normoxic conditions. On the other hand, BEC were not affected by concentrations of carbon tetrachloride or 7-ethoxycoumarin that are known to exert toxic effects on hepatocytes. The development of both menadione- and cumene hydroperoxide-induced toxic injury in BEC followed a common and time-correlated pattern, and included a strong depletion of GSH, depletion of protein thiols and an increase in the extent of cell death. The damage induced by cumene hydroperoxide was found to be independent of lipid peroxidative processes and was prevented by a pre-incubation with desferrioxamine. The cytotoxicity of menadione was further exacerbated by dicoumarol but was not prevented by desferrioxamine or promethazine. The mechanisms underlying BEC injury and death induced by the quinone and by the organic hydroperoxide are discussed in relation to the known biochemical characteristics of BEC.

Animals↗
PubMed1990

Comparative evaluation of the antioxidant activity of alpha-tocopherol, alpha-tocopherol polyethylene glycol 1000 succinate and alpha-tocopherol succinate in isolated hepatocytes and liver microsomal suspensions.

The antioxidant activity of alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) and of alpha-tocopherol succinate (TS) has been examined in isolated hepatocytes and microsomal fractions from rat liver. Both TPGS and TS require esterase activity to yield free alpha-tocopherol and, hence, antioxidant activity. TPGS and TS consistently exerted a more effective antioxidant protection than an equivalent amount of directly-added free alpha-tocopherol. The low antioxidant efficiency of directly added free alpha-tocopherol in such water-based experimental systems as used here seems to be due to its extreme hydrophobicity. TPGS, on the other hand, is an extremely hydrophilic compound that is being examined as a useful source of alpha-tocopherol in certain clinical situations and is here shown to be a convenient and effective source for experimental studies into lipid peroxidation and antioxidant mechanisms.

Animals↗
PubMed1990

Studies on the hyperplasia ('regeneration') of the rat liver following partial hepatectomy. Changes in lipid peroxidation and general biochemical aspects.

Using the experimental model of partial hepatectomy in the rat, we have examined the relationship between cell division and lipid peroxidation activity. In rats entrained to a regime of 12 h light/12 h dark and with a fixed 8 h feeding period in the dark phase, partial hepatectomy is followed by a rapid regeneration of liver mass with cycles of synchronized cell division at 24 h intervals. The latter phenomenon is indicated in this study by pulses of thymidine kinase activity having maxima at 24 h, 48 h and 72 h after partial hepatectomy. Microsomes prepared from regenerating livers show changes in lipid peroxidation activity (induced by NADPH/ADP/iron or by ascorbate/iron), which is significantly decreased relative to that in microsomes from sham-operated controls, again at 24 h, 48 h and 72 h after the operation. This phenomenon has been investigated with regard to possible underlying changes in the content of microsomal fatty acids, the microsomal enzymes NADPH:cytochrome c reductase and cytochrome P-450, and the physiological microsomal antioxidant alpha-tocopherol. The cycles of decreased lipid peroxidation activity are apparently due, at least in part, to changes in microsomal alpha-tocopherol content that are closely associated in time with thymidine kinase activity.

Animals↗