A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome.

Breast cancer in men is rare--among the risk factors that have been identified are a family history of breast cancer and evidence of androgen insufficiency. We report a family in which two brothers who both developed breast cancer had clinical and endocrinological evidence of androgen resistance. Sequence analysis revealed a mutation in the androgen receptor gene on the X chromosome, within the region encoding the DNA binding domain. This is the first report of a germline mutation in a member of the steroid/thyroid hormone receptor superfamily associated with the development of cancer.

Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13.

A small proportion of breast cancer, in particular those cases arising at a young age, is due to the inheritance of dominant susceptibility genes conferring a high risk of the disease. A genomic linkage search was performed with 15 high-risk breast cancer families that were unlinked to the BRCA1 locus on chromosome 17q21. This analysis localized a second breast cancer susceptibility locus, BRCA2, to a 6-centimorgan interval on chromosome 13q12-13. Preliminary evidence suggests that BRCA2 confers a high risk of breast cancer but, unlike BRCA1, does not confer a substantially elevated risk of ovarian cancer.

Tissue-specific pharmacodynamics of 5-bromo-2'-deoxyuridine incorporation into DNA in VX2 tumor-bearing rabbits.

The thymidine analog 5-bromo-2'-deoxyuridine (BrdUrd) is felt to exert its cytotoxic effects primarily through incorporation into DNA. We have evaluated the incorporation of BrdUrd into the DNA of relevant normal tissues (bone marrow, gut mucosa, and liver) and tumor in rabbits with the VX2 tumor growing intrahepatically. Using constant i.v. infusions, steady state plasma drug concentrations ranging from 0.4 to 65.4 microM were maintained for 24 h and tissues were harvested and processed so that a sensitive gas chromatography/mass spectrometry (GC/MS) method could be used to analyze the thymine and 5-bromouracil content of hydrolyzed DNA. In all tissues, DNA incorporation showed saturating effects as plasma BrdUrd concentration was increased and, BrdUrd incorporation as a function of plasma concentration could be fitted to a Langmuir-like equation generating tissue-specific pharmacodynamic parameters: Imax for percentage thymine replacement at infinite plasma BrdUrd concentrations, and C50 for the arterial BrdUrd concentration generating incorporation that is Imax/2. At all plasma concentrations of BrdUrd the incorporation into DNA of bone marrow was greater than that observed in VX2 tumor. However, BrdUrd labeling index (with a BrdUrd monoclonal antibody) was greater in tumor than bone marrow. Thus, pharmacodynamic differences in incorporation do not result solely from cytokinetic differences between tissues. This model may prove useful in evaluating the pharmacodynamics of incorporation in studies using hepatic arterial infusion and biochemical modulation to improve selectivity.

Constitutional mutation in exon 8 of the p53 gene in a patient with multiple primary tumours: molecular and immunohistochemical findings.

We report a constitutional mutation of codon 273 in exon 8 of the p53 gene. The affected individual has developed multiple independent benign and malignant tumours (tricholemmoma of the scalp, multiple trichoepitheliomata of the face, osteosarcoma of the ovary, bilateral breast cancer, malignant fibrous histiocytoma of the thigh and endometrial adenocarcinoma) and belongs to a family with some, but not all, features of the Li-Fraumeni syndrome. The mutation, found in both blood lymphocyte and tumour specimens, is a cytosine to thymine transition at codon 273, resulting in an amino acid change from arginine to cysteine. The mother and sister of the index case both died of tumours at an early age. We have demonstrated that formalin-preserved material from these tumours contains the same C-->T mutation at codon 273, indicating that this mutation has probably been transmitted through the germline. All tumours from the index case, both benign and malignant, showed immunohistochemical positivity with four antibodies to the p53 protein. Positive staining was also seen in scattered nuclei of morphologically normal epidermal keratinocytes and pilosebaceous cells, but not in lymphocytes or other morphologically normal cells from the index case. However, a similar staining pattern in apparently normal tissue was also observed in 13/48 sections from other individuals with various skin conditions (melanocytic naevi, psoriasis and normal skin adjacent to malignant melanoma and fibrous histiocytomas), suggesting that this pattern of p53 staining may not be unique to individuals with constitutional p53 mutations.

No evidence for germline mutations in exons 5-9 of the p53 gene in 25 breast cancer families.

Recent studies have demonstrated that families with the Li-Fraumeni syndrome carry inherited point mutations of the p53 gene. In the present study 25 families with strong histories of breast cancer were screened for the presence of such mutations. Polymerase chain reaction products of exons 5-9 of the p53 gene were examined by single-stranded conformational polymorphism analysis and, in addition, exon 7 was further screened by direct sequencing. No mutations were detected in constitutive DNA by either method. These results indicate that familial breast cancer does not usually result from germline point mutations in the p53 gene.

Inherited necrotizing myelopathy of Afghan hounds.

Eleven examples of a naturally occurring, adolescent-onset spinal cord necrosis in Afghan Hounds were studied. Unusual and characteristic spinal cord lesions were necrosis and small vessel proliferation in the dorsal and ventro-medial spinal cord white matter extending from caudal cervical segments to cranial lumbar segments. Spinal cord gray matter and dorsal and ventral roots were preserved. Four dogs had histologically similar lesions in the superior olivary nucleus. The cause of these lesions was not determined by histopathologic or ultrastructural examination. Chi-square analysis of pooled sibships indicates a simple autosomal recessive mode of inheritance.

Do primary dysfunctions in neural control of arterial pressure contribute to hypertension?

This article is a summary of the physiological and clinical evidence that links the cause of essential hypertension to the brain. We stress the potential importance of a biochemical disturbance in the central role of angiotensin II in the regulation of arterial pressure. While the evidence is compelling, we acknowledge the need for further complete studies on this timely subject.

Metabotropic glutamate receptors in the ventrolateral medulla of rats.

We investigated the hypothesis that stimulation of metabotropic excitatory amino acid receptors in the ventrolateral medulla evokes cardiovascular responses. Thus, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD], a selective agonist of metabotropic excitatory amino acid receptors, was microinjected into the rostral or caudal ventrolateral medulla of halothane-anesthetized Sprague-Dawley rats. Microinjections of (1S,3R)-ACPD (100 pmol-1 nmol) into the rostral ventrolateral medulla produced dose-dependent increases in mean arterial pressure (+20 +/- 4 mm Hg by 100 pmol and +35 +/- 2 mm Hg by 1 nmol, p < 0.01 versus artificial cerebrospinal fluid) and integrated splanchnic sympathetic nerve activity (+17 +/- 3% and +46 +/- 4%, respectively, p < 0.01), whereas (1S,3+)-ACPD microinjected into the caudal ventrolateral medulla decreased mean arterial pressure (-28 +/- 2 mm Hg by 100 pmol and -48 +/- 6 mm Hg by 1 nmol, p < 0.01 versus artificial cerebrospinal fluid) and splanchnic sympathetic nerve activity (-24 +/- 4% and -49 +/- 5%, p < 0.01). The blockade of ionotropic excitatory amino acid receptors by the combined injection of 2-amino-7-phosphonoheptanoic acid (200 pmol) and 6,7-dinitroquinoxaline-2,3-dione (200 pmol), which effectively blocked the responses elicited by either N-methyl-D-aspartate (20 pmol) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (5 pmol), failed to affect the responses evoked by either (1S,3R)-ACPD (100 pmol) or L-glutamate (2 nmol) microinjected in the rostral and caudal ventrolateral medulla. These results suggest that metabotropic receptors are present and mediate cardiovascular responses evoked by L-glutamate injections into the rostral and caudal ventrolateral medulla.

Role of nitric oxide and angiotensin II in the regulation of sympathetic nerve activity in spontaneously hypertensive rats.

This study evaluated the actions of nitric oxide on the blood pressure and renal sympathetic nerve activity responses produced by angiotensin II (Ang II) blockade in conscious spontaneously hypertensive rats. Two days after implantation of electrodes, we measured mean arterial pressure, heart rate, and renal sympathetic nerve activity. Baroreceptor reflex function was assessed with a logistic function curve; the maximum slope of the curve estimated the baroreceptor reflex gain. Data were obtained in rats given acute intravenous administration of either vehicle, the Ang II type 1 receptor antagonist losartan, the type 2 antagonist CGP 42112A, or the converting enzyme inhibitor lisinopril. In comparison with vehicle (-1.1 +/- 0.2%/mm Hg), both losartan (-1.8 +/- 0.3%/mm Hg) and lisinopril (-2.4 +/- 0.2%/mm Hg) significantly increased the maximum gain of the baroreceptor reflex control of nerve activity (p < 0.05). In contrast, the type 2 receptor antagonist did not alter baroreceptor reflex function. Similar studies were performed in rats that received an intravenous injection of NG-monomethyl L-arginine (10 mg/kg). The nitric oxide synthase inhibitor increased baseline blood pressure and decreased renal sympathetic nerve activity. Subsequent administration of losartan or lisinopril returned blood pressure to initial hypertensive level, whereas sympathetic nerve activity was increased to a level above the initial control value. The maximum gain of the baroreceptor reflex control of renal nerve activity was increased after the nitric oxide inhibition. The present study demonstrates that blunted baroreceptor reflex function in conscious spontaneously hypertensive rats is mediated by an Ang II type 1 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular actions of vasopressin at the ventrolateral medulla.

Vasopressin acts at a number of sites in the central nervous system to alter arterial pressure. This study investigated the hypothesis that vasopressin acts at the rostral ventrolateral medulla to increase arterial pressure. The rostral pressor area of the medulla oblongata was exposed in urethane-anesthetized rats prepared for topical application of vasopressin. A 3-minute application of vasopressin (range 10(-8) to 10(-3) M) produced dose-dependent increases in arterial pressure that averaged between 2 +/- 1 and 65 +/- 11 mm Hg (p less than 0.01). Tachycardia was not a consistent response at any concentration of vasopressin. Intravenous administration of a V1 vasopressin antagonist did not modify the pressor response produced by topical application of vasopressin (10(-4) M). Application of the V1 antagonist to the rostral pressor area, however, prevented the production of a pressor effect to subsequent topical application of vasopressin (10(-4) M). These experiments suggest that vasopressin stimulates the activity of vasomotor neurons in the rostral ventrolateral medulla by a mechanism that involves a neuronal V1 receptor.

Role of area postrema in transgene hypertension.

Transgenic [Tg(+)] rats carrying the mouse Ren-2d gene [(mRen-2d)27] are a newly established monogenetic form of experimental hypertension. To determine whether the area postrema contributes to the development of hypertension in mRen-2 Tg(+) rats, this circumventricular organ in the fourth ventricle was removed from 5-week-old Tg(+) rats. From weeks 4 through 9, systolic blood pressure was measured weekly by tail-cuff plethysmography in area postrema-lesioned and sham-lesioned Tg(+) rats. Although systolic blood pressure rose markedly in sham-lesioned Tg(+) rats, the increase in systolic blood pressure was significantly attenuated in area postrema-lesioned Tg(+) rats. At 9 weeks of age, a femoral artery was cannulated for the measurement of arterial pressure in awake rats. Mean arterial pressure (MAP) in area postrema-lesioned Tg(+) rats was significantly (P < .01) lower than that in sham-lesioned rats: 171 +/- 7 and 132.+/- 5 mm Hg, respectively. Baroreceptor reflex was evaluated by intravenous infusion of sodium nitroprusside. There was no significant difference in baroreceptor reflex sensitivity between the two groups. Intravenous pentolinium (5 mg/kg), used to produce sympathetic ganglionic block, caused significant decreases in MAP in both groups. However, the reduction of MAP in the sham-lesioned group was significantly (P < .05) greater than that in the area postrema-lesioned group: -73 +/- 4 and -48 +/- 6 mm Hg, respectively. The ratio of left ventricular weight to body weight in sham-lesioned Tg(+) rats was significantly larger than that of area postrema-lesioned rats. These results suggest that ablation of the area postrema markedly attenuates the development of hypertension in mRen-2d Tg(+) rats, and this attenuation may be attributed to decrease in sympathetic outflow.

The ventrolateral medulla. A new site of action of the renin-angiotensin system.

High-affinity binding sites for angiotensin II (Ang II) in the ventrolateral medulla suggest that Ang II may act at cell groups that are known to modulate blood pressure. This hypothesis was investigated by the topical application of angiotensin I (Ang I), Ang II, the Ang II antagonist [Sar1, Thr8]Ang II, and the Ang I converting enzyme inhibitor MK 422 to a restricted region of the ventral medullary surface known as the glycine-sensitive area. Both Ang I (100 pmol) and Ang II (100 pmol) produced significant (p less than 0.01) increases in blood pressure (+20 +/- 4 and +31 +/- 5 mm Hg, respectively) that were associated with no change in heart rate. Furthermore, the relationship between the peak increases in blood pressure and Ang II was dose-dependent. Blockade of endogenous Ang II by [Sar1, Thr8]Ang II (13 nmol) produced a significant decrease in baseline blood pressure (-8 +/- 1 mm Hg; p less than 0.001). Similarly, topical application of MK 422 prevented the pressor effect of Ang I. Taken together, these experiments indicate that at least some components of the renin-angiotensin system exist in the ventrolateral medulla and they may modulate vasomotor outflow.

Vasodepressor actions of angiotensin-(1-7) unmasked during combined treatment with lisinopril and losartan.

Blockade of angiotensin II (Ang II) function during 8 days of oral therapy with lisinopril (20 mg/kg) and losartan (10 mg/kg) normalized the arterial pressure (112+/-3/70+/-3 mm Hg) and raised the plasma concentrations of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] of 21 male spontaneously hypertensive rats (SHR). Treated animals were then given a 15-minute infusion of either mouse immunoglobulin G1 or a specific monoclonal Ang-(1-7) antibody while their blood pressure and heart rate were recorded continuously in the awake state. The concentrations of Ang II and Ang-(1-7) in arterial blood were determined by radioimmunoassay. Infusion of the Ang-(1-7) antibody caused significant elevations in mean arterial pressure that were sustained for the duration of the infusion and were accompanied by transient bradycardia. Although the hemodynamic effects produced by infusion of the Ang-(1-7) antibody had no effect on plasma levels of Ang II, they caused a twofold rise in the plasma concentrations of Ang-(1-7). A pressor response of similar magnitude and characteristics was obtained in a separate group of SHR treated with the combination of lisinopril and losartan for 8 days during an infusion of [Sar1-Thr8]Ang II. The pressor response induced by the administration of this competitive, non-subtype-selective Ang II receptor blocker was not modified by pretreatment of the rats with an angiotensin type-2 (AT2) receptor blocker (PD123319). Plasma concentrations of Ang II and Ang-(1-7) were not changed by the administration of [Sar1-Thr8]Ang II either in the absence or in the presence of PD123319 pretreatment. These results are the first to indicate an important contribution of Ang-(1-7) in mediating the vasodilator effects caused by combined inhibition of angiotensin-converting enzyme and AT1 receptors. The comparable results obtained by administration of [Sar1-Thr8]Ang II suggest that the vasodepressor effects of Ang-(1-7) during the combined treatment is modulated by a non-AT1/AT2 angiotensin subtype receptor.

Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer's disease is related to the apolipoprotein E genotype.

A great number of epidemiological studies have demonstrated that the frequency of the epsilon4 allele of the apolipoprotein E gene (APOE) is markedly higher in sporadic and in familial late onset Alzheimer disease (AD). In the frontal cortex of AD patients, oxidative damage is elevated. We address the hypothesis that the APOE genotype and reactive oxygen-mediated damage are linked in the frontal cortex of AD patients. We have related the APOE genotype to the levels of lipid oxidation (LPO) and to the antioxidant status, in frontal cortex tissues from age-matched control and AD cases with different APOE genotypes. LPO levels were significantly elevated in tissues from Alzheimer's cases which are homozygous for the epsilon4 allele of APOE, compared to AD epsilon3/epsilon3 cases and controls. Activities of enzymatic antioxidants, such as catalase and glutathione peroxidase (GSH-PX), were also higher in AD cases with at least one epsilon4 allele of APOE, while superoxide dismutase (SOD) activity was unchanged. In the frontal cortex, the concentration of apoE protein was not different between controls and AD cases, and was genotype independent. The Ginkgo biloba extract (EGb 761), the neurosteroid dehydroepiandrosterone (DHEA) and human recombinant apoE3 (hapoE3rec) were able to protect control, AD epsilon3/epsilon3 and epsilon3/epsilon4 cases against hydrogen peroxide/iron-induced LPO, while hapoE4rec was completely ineffective. Moreover, EGb 761 and DHEA had no effect in homozygous epsilon4 cases. These results demonstrate that oxidative stress-induced injury and protection by antioxidants in the frontal cortex of AD cases are related to the APOE genotype.

Quantitative analysis of the dendrites of cat phrenic motoneurons stained intracellularly with horseradish peroxidase.

All the dendrites (N = 37) generated by four phrenic motoneurons were analyzed following intracellular injection of horseradish peroxidase. The dendritic arbors produced from each of these stem dendrites were studied in detail. The mean number of stem dendrites produced by a phrenic motoneuron was 9.7, their mean diameter was 6.0 micron, and their mean combined diameter was 58.3 micron. The length at which a phrenic motoneuronal dendrite terminated was 1,236 micron, with several end terminals extending more than 2 mm from the cell body. The mean value for the combined lengths of all segments originating from a single stem dendrite was 5.3 mm. A full spectrum of dendritic branching patterns was observed from simple (five unbranched) to complex, the latter producing up to ninth-order branches. Most terminal and nonterminal dendritic segments tapered, producing a mean diameter reduction of 34%, or approximately 9% per 100-micron length. All phrenic motoneurons exhibited a steady decrease in the combined dendritic parameter (sigma d3/2) with distance from the soma as a result of tapering and end-branch termination. The mean surface area and volume of a phrenic motoneuronal dendrite were 35.3 X 10(3) micron 2 and 25.9 X 10(3) micron 3, respectively. The dendrites constituted greater than 97% of the total phrenic motoneuronal surface area, with 75% of this area lying outside of a 300-micron radius from the cell body. The diameter of a stem dendrite was positively correlated with its combined dendritic length, number of terminal branches, dendritic surface area, and volume. Despite this strong correlation, the value of total dendritic surface area calculated using the power equation derived from the dendritic surface area versus stem dendritic diameter plot was not a consistent estimator of the total dendritic surface area directly measured for these four phrenic motoneurons. It is suggested that this inconsistency may be the result of a heterogeneity in the phrenic motoneuronal population and/or in the dendrites projecting to the different terminal fields.

Morphology of inspiratory neurons located in the ventrolateral nucleus of the tractus solitarius of the cat.

The morphology of 11 dorsal respiratory group (DRG) inspiratory neurons located in the ventrolateral nucleus of the solitary tract (vl-NTS) was studied using the technique of intracellular labeling with the enzyme horseradish peroxidase (HRP). Six of these cells were cut in the transverse plane and had a mean somal diameter of 30.4 micron, while five others sectioned in the horizontal plane had a mean of 38.2 micron. These neurons produced an average of 6.2 primary dendrites (range: 4-10), many of which projected rostrally or caudally up to 1.0 mm from the cell bodies. These dendrites were oriented along the longitudinal axis; they ran parallel and ventral to the tractus solitarius. In general, all dendrites possessed numerous spines and appendages. Many axons could be traced for considerable distances within the medulla (in one instance, up to 8 mm). These axons were last discerned in the contralateral ventral medulla rostral to the level of their cell bodies. The axons of three neurons bifurcated in the ipsilateral medulla; one branch remained ipsilateral and projected caudally, while the other crossed the midline. A small number of counterstained cells of size similar to or larger than the HRP-stained neurons formed a column that constituted the vl-NTS. Based upon our observations of stained and counterstained cells, we conclude that the inspiratory neurons of the vl-NTS are few in number and represent a morphologically homogeneous population. The primary orientation of the dendritic arbors of vl-NTS inspiratory neurons appears to optimize the surface area available to receive synaptic contacts from sensory afferents emerging from the tractus solitarius.

Morphology of cat phrenic motoneurons as revealed by intracellular injection of horseradish peroxidase.

The morphology of phrenic motoneurons (PMs) of adult cat was examined by utilizing the technique of intracellular injection of horseradish peroxidase. Twenty-one cells were reconstructed from serial sections in transverse, sagittal, and horizontal planes. The cell bodies were ellipsoid, with the major diameter oriented parallel to the longitudinal axis of the spinal cord. The dendrites of PMs are not distributed in a radially symmetric fashion, but rather project to four separate fields. The field containing the greatest number of dendrites extends rostrocaudally within the phrenic motor column. This collection of dendrites forms a rostrocaudal bundle in which the dendrites from neighboring PMs lie in close association with one another. The remaining dendrites project dorsolaterally, dorsomedially, and to a lesser extent, ventrally. The dorsolaterally directed dendrites from bundles upon entering the lateral funiculus with the dendrites from other PMs. Several of the dorsomedially directed dendrites cross to the contralateral spinal cord via the anterior commissure or central gray. A wide variety of dendritic spines and appendages was observed. There were not instances in which axon collaterals were observed for the 11 well-stained axons examined. The length of the initial segment of the axon was a function of the distance of the cell body from the ventral funiculus.

Initial coronary air embolus in the differential diagnosis of coronary artery spasm.

Angiographic and electrocardiographic manifestations of initial coronary air embolism were seen in 4 patients and in a dog. All 4 patients had angina pectoris, 2 had ST elevation, 1 patient had ST depression and 1 had no electrocardiographic change after the air embolus. Although the initial diagnosis in these 4 patients was coronary artery spasm, a subsequent ergonovine test response for coronary artery spasm was negative in the 3 patients in whom it was performed. In a dog, initial injection of air in a coronary artery produced ST-segment elevation and delayed clearance of contrast material. The angiographic appearance of initial air embolus was similar in the 4 patients and in the dog. The leading edge of contrast material that followed an air embolus stopped abruptly, appeared hazy and blunt, and pulsated back and forth. The air embolus produced temporary cessation of flow in the main artery and its branches. Initial injection of air during coronary arteriography mimics coronary artery spasm by producing a syndrome characterized by angina, ischemic changes on the electrocardiogram, and delayed flow of contrast material. An initial air embolus may be differentiated from true coronary spasm by several distinctive angiographic features.

Melphalan resistance and photoaffinity labelling of P-glycoprotein in multidrug-resistant Chinese hamster ovary cells: reversal of resistance by cyclosporin A and hyperthermia.

The multidrug resistance phenotype is often associated with overexpression of P-glycoprotein, an energy-dependent efflux pump responsible for decreased intracellular accumulation of chemotherapeutic agents. The role of P-glycoprotein in the mechanism of cross-resistance to melphalan in multidrug-resistant Chinese hamster ovary cells (CH(R)C5) was investigated by photoaffinity labelling of P-glycoprotein using [3H]azidopine. We investigated whether the chemosensitiser cyclosporin A and hyperthermia, either used alone or combined, could reverse melphalan resistance and alter transport processes for [14C]melphalan in CH(R)C5 cells. Melphalan inhibited azidopine photolabelling of P-glycoprotein, implicating drug efflux mediated by P-glycoprotein in the mechanism of melphalan resistance in CH(R)C5 cells. Azidopine photolabelling also was inhibited by the chemosensitiser cyclosporin A, which binds to P-glycoprotein. Cyclosporin A alone reversed melphalan resistance in CH(R)C5 cells, but had no effect in drug-sensitive AuxB1 cells. Hyperthermia (40-45 degrees) alone increased melphalan cytotoxicity in both cell lines. When hyperthermia was combined with cyclosporin A, a large increase in melphalan cytotoxicity occurred, but only in CH(R)C5 cells. This effect increased with temperature and exposure time. Sensitisation to melphalan cytotoxicity by heat and cyclosporin A in CH(R)C5 cells appeared to be explained by altered drug transport processes. Lower accumulation of melphalan occurred in CH(R)C5 cells than in drug-sensitive cells. At 37 degrees, cyclosporin A increased drug accumulation in CH(R)C5 cells, but not in AuxB1 cells, by slowing drug efflux from cells. Heat alone increased both melphalan uptake and drug efflux for both cell lines. Our findings suggest that the combination of cyclosporin A and hyperthermia could be very useful in overcoming melphalan resistance by increasing intracellular drug accumulation in multidrug-resistant cells.

Impact of apoE deficiency on oxidative insults and antioxidant levels in the brain.

Apolipoprotein E (apoE) is a lipid transport molecule, which has been linked to the pathogenesis of Alzheimer's disease. Recently we have demonstrated that the oxidative insults in hippocampus from AD patients were dependent on the apoE genotype. Interestingly, apoE protein concentration in hippocampus follows a genotype-dependent gradient with the lowest level occurring in varepsilon4 allele carrier. We raised the possibility that, in the hippocampus, the apoE level affects the oxidant/antioxidant balance. Here, we have examined in the apoE-deficient mouse the oxidant/antioxidant status in hippocampus and in frontal cortex from APOE-KO and wild-type mice at 3 and 13 months. We provided evidence that, in the hippocampus, the absence of apoE has a clear impact on the oxidant/antioxidant status. Endogenous level of thiobarbituric acid-reactive substances (TBARS) was found to be markedly elevated whereas level of alpha-tocopherol was decreased in APOE-deficient mice at 3 and 13 months. Superoxide dismutase activities were also lower in APOE-deficient mice at 13 months. Taken together, these data indicate that the steady state level of apoE may influence, to a certain extent, the balance between oxidants and antioxidants in hippocampus.