Genotoxicity of estrogens

 Genotoxic effect of the endogenous mammalian estrogen 17β-estradiol and the synthetic estrogen diethylstilbestrol have recently been demonstrated, e. g. the induction of numerical chromosome aberrations (aneuploidy, i. e., the condition in which one or more whole chromosomes of a normal set are missing or present in more than the usual set of copies) and the formation of deoxyribonucleic acid (DNA) adducts. It is likely that the genotoxicity of the estrogens acts in concert with their hormonal activity to give rise to their carcinogenic effects. Many of the phytoestrogens that occur in plants and the numerous anthropogenic estrogens in our environment, which are ingested with food, have not yet been examined for their genotoxic potential. Recent studies have demonstrated that some but not all of these estrogens exhibit genotoxicity. The type and strength of the genotoxicity strongly depends on the chemical structure and does not correlate with estrogenicity. For example, coumestrol and genistein are clastogenic in cultured mammalian cells and lead to gene mutations, whereas biochanin-A and bisphenol-A have the potential to cause aneuploidy. Daidzein, enterolactone, enterodiol and certain bisphenols are devoid of genotoxic effects. The genotoxicity should be determined individually for each estrogen and taken into account in the assessment of its carcinogenic risk. Received: 19 December 1997     

A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study

BACKGROUND: There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer's disease. METHODS: We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimer's disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3). RESULTS: Despite random assignment, the baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups, and this variable was highly predictive of the primary outcome (P<0.001). In the unadjusted analyses, there was no statistically significant difference in the outcomes among the four groups. In analyses that included the base-line score on the Mini-Mental State Examination as a covariate, there were significant delays in the time to the primary outcome for the patients treated with selegiline (median time, 655 days; P=0.012), alpha-tocopherol (670 days, P=0.001) or combination therapy (585 days, P=0.049), as compared with the placebo group (440 days). CONCLUSIONS: In patients with moderately severe impairment from Alzheimer's disease, treatment with selegiline or alpha-tocopherol slows the progression of disease.     

Restricted geographical extension of the association of a glucagon receptor gene mutation (Gly40Ser) with non-insulin-dependent diabetes mellitus

In the present work the effects of i.c.v. administration of La3+ and Gd3+ on the motor stimulant effect of cocaine in rats were studied. Both La3+ and Gd3+ failed to influence basal motor activity. However, the two metal ions differ in modulation of cocaine-induced activation of motor activity. While Gd3+ (10.0, 20.0 and 40.0 mM/1 ml) did not influence significantly the cocaine effect, La3+ (0.1, 1.0 and 10 mM/1 ml) inhibited cocaine-induced motor activation in a dose-dependent manner. The results suggest the possible involvement of La(3+)-but not Gd(3+)-sensitive calcium channels in the locomotor stimulant effect of cocaine.     

Allgemeine Technologie der Lebensmittel, Vorratspflege

Ohne Zusammenfassung     

Aromatic hydroxylation is a major metabolic pathway of the mycotoxin zearalenone in vitro

Zearalenone (ZEN) is a common mycotoxin, for which only reductive metabolites have been identified so far. We now report that ZEN is extensively monohydroxylated by microsomes from human liver in vitro. Two of the major oxidative metabolites arise through aromatic hydroxylation and are catechols. Their chemical structures have been unambiguously determined by using deuterium‐labeled ZEN and by comparison with authentic reference compounds. Moreover, both catechol metabolites of ZEN were substrates of the enzyme catechol‐O‐methyl transferase. One of the monomethyl ethers represented the major metabolite when ZEN was incubated with rat liver slices, thus demonstrating that catechol formation also takes place under in vivo‐like conditions. Out of ten major human cytochrome P450 (hCYP) isoforms only hCYP1A2 was able to hydroxylate ZEN to its catechols with high activity. Catechol formation represents a novel pathway in the metabolism of ZEN and may be of toxicological relevance.     

Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione

Deficiency of the antioxidant glutathione in brain appears to be connected with several diseases characterized by neuronal loss. To study neuronal glutathione metabolism and metabolic interactions between neurons and astrocytes in this respect, neuron-rich primary cultures and transient cocultures of neurons and astroglial cells were used. Coincubation of neurons with astroglial cells resulted within 24 hr of incubation in a neuronal glutathione content twice that of neurons incubated in the absence of astroglial cells. In cultured neurons, the availability of cysteine limited the cellular level of glutathione. During a 4 hr incubation in a minimal medium lacking all amino acids except cysteine, the amount of neuronal glutathione was doubled. Besides cysteine, also the dipeptides CysGly and gammaGluCys were able to serve as glutathione precursors and caused a concentration-dependent increase in glutathione content. Concentrations giving half-maximal effects were 5, 5, and 200 microM for cysteine, CysGly, and gammaGluCys, respectively. In the transient cocultures, the astroglia-mediated increase in neuronal glutathione was suppressed by acivicin, an inhibitor of the astroglial ectoenzyme gamma-glutamyl transpeptidase, which generates CysGly from glutathione. These data suggest the following metabolic interaction in glutathione metabolism of brain cells: the ectoenzyme gamma-glutamyl transpeptidase uses as substrate the glutathione released by astrocytes to generate the dipeptide CysGly that is subsequently used by neurons as precursor for glutathione synthesis.