Search NEL Online

Journal Article 2014; 35(Suppl 2): 158-168 PubMed PMID: 25638381 Citation  Keywords:  Animals, Benzo(a)pyrene:administration & dosage, Carcinogens:administration & dosage, DNA Adducts:administration & dosage, Flavonols:administration & dosage, Male, Rats, Rats, Wistar,.   

OBJECTIVES: Flavanol dihydromyricetin (DHM) has been shown to counteract acute ethanol (EtOH) intoxication and reduce excessive EtOH consumption. Since this flavonoid is being considered for human use, the in vivo study of DHM interactions with the cytochrome P450 (CYP) multienzyme system in the respect of metabolic activation of a model food-born carcinogen, benzo[a]pyrene (BaP), is of high importance. Flavonoids of known properties, alpha-naphthoflavone (ANF) and beta-naphthoflavone (BNF) were included into the study to compare their and DHM effects on BaP-DNA adduct formation. METH0 DS: The flavonoids were administered by oral gavage either 72 hrs prior or simultaneously with a single dose of BaP to experimental rats. The expression of CYP1A1/2 enzymes was examined based on the enzymatic activity with a marker substrate, 7-ethoxyresorufin, and on Western blots. The nuclease P1 version of the 32P-postlabeling assay was used to detect and quantify covalent DNA adducts formed by BaP.

RESULTS: Treatment of rats with a single dose of DHM or ANF prior to or simultaneously with BaP did not produce an increase in levels of CYP1A1 and in formation of BaP-DNA adducts in liver. BNF, a known inducer of CYP1A1, showed a synergistic effect on BaP-mediated CYP1A1 induction and BaP activation in liver. Contrary to that, in small intestine the stimulatory effect of BNF on both parameters was not detected. Animal pre-treatment with DHM or ANF before BaP administration resulted in a significant elevation of BaP-DNA adducts, namely in the distal part of small intestine, while the CYP1A1 mediated 7-ethoxyresorufin-O-deethylation (EROD) was decreased markedly. It is important to note that under all regimens of animal treatment, DHM or ANF produced the higher inhibitory effect on the BaP-DNA adduct formation and BaP-induced EROD activity of CYP1A1 when administered simultaneously than sequentially with BaP. Our data show that DHM or ANF did not enhance the BaP-activation leading to BaP-mediated genotoxicity (the formation of BaP-DNA adducts) in rat liver, however, in small intestine the pretreatment of rats with these flavonoids may enhance BaP genotoxicity.

CONCLUSIONS: The data indicate that the intake of DHM prior to or simultaneously with the administration of BaP may increase the risk of a BaP-induced tumorigenesis in small intestine.

...

Read abstract  Full text PDF

Journal Article 2005; 26(1): 51-54 PubMed PMID: 15726020 Citation  Keywords:  Animals, Carcinogens:administration & dosage, Cell Survival:drug effects, Diethylstilbestrol:administration & dosage, Drug Implants, Hypoglycemic Agents:pharmacology, Ligands, Male, PPAR gamma:drug effects, Pituitary Neoplasms:chemically induced, Prolacti.   

OBJECTIVES: PPAR-gamma is a member of the nuclear receptor superfamily. PPAR-gamma activation is associated with glucose metabolism regulation, adipocyte differentiation, inhibition of macrophage and monocyte activation and anti-angiogenesis. PPAR-gamma ligands thiazolidinediones (TZDs) have been shown to inhibit the growth and secretory activity of several rat and murine pituitary tumors in vivo as well as in vitro (ACTH-secreting AtT20, PRL- and GH-secreting GH3, LH-secreting LbetaT2 and alpha-T3 cells). TZDs have been demonstrated to induce G0-G1 cell-cycle arrest and apoptosis in human, rat somatolactotroph, murine corticotroph and gonadotroph pituitary tumor cells. In the present study we have investigated for the first time the effects of PPAR-gamma receptor ligand rosiglitazone on the rat estrogens-induced, PRL-secreting pituitary tumor cells in vitro.

MATERIAL AND METHODS: Four weeks old male Fischer 344 rats were used in the experiment. Pituitary tumors were induced by subcutaneous implantation of capsules containing diethylstilboestrol (DES). Eight weeks after the implantation of capsules the rats were sacrificed and pituitary tumors were collected. Tumorous cells were isolated and exposed in the primary culture to rosiglitazone at the concentrations 10(-10) - 10(-4)M for 24 hours. The cell growth was estimated by the measurement of the cells metabolic activity using the EZ4U system.

RESULTS: We have demonstrated that rosiglitazone at the concentrations 10(-10) - 10(-4)M significantly decreases the number of viable rat PRL-secreting pituitary tumor cells in vitro.

CONCLUSION: These results suggest that PPAR-gamma receptor agonists thiazolidinediones may be useful in the medical treatment of pituitary tumors....

Read abstract  Full text PDF

Comparative Study 2001; 22(4): 229-237 PubMed PMID: 11524628 Citation  Keywords:  1,2-Dimethylhydrazine:administration & dosage, Animals, Biogenic Monoamines:metabolism, Carcinogens:administration & dosage, Circadian Rhythm:drug effects, Dopamine:metabolism, Drug Administration Schedule, Female, Hydroxyindoleacetic Acid:metabolism, Inj.   

OBJECTIVES: Our data on the contents of norepinephrine (NE), dopamine (DA) and the metabolite of serotonin 5-hydroxyindoleacetic acid (5-HIAA) measured in the suprachiasmatic nuclei (SCN), preoptic area (PA) and median eminence (ME) of hypothalamus of rats after single subcutaneous injection of 1,2-dimethylhydrazine (DMH) as well as the effect of this carcinogen on formation of reactive oxygen species (ROS) in the PA are presented in this paper.

RESULTS: Diurnal changes of DA in all studied brain structures and of NE in the PA have been observed in the control group. Their morning levels were higher than evening ones. Rhythms of 5-HIAA in the SCN and diurnal changes of ROS formation have been shown to have contrary changes in control. Both the morning (11 a.m.) and evening (11 p.m.) subcutaneous administration of DMH at the dose of 21 mg/kg of body weight resulted in changes of all rhythms observed in control. In some cases a phase shift was found, in others the rhythms of neurotransmitters and ROS formation disappeared entirely.

CONCLUSION: The data obtained confirm the idea of dopaminergic and serotoninergic systems taking part in mechanisms of a response of the hypothalamic nuclei to non-photic stimuli. It is suggested that the effect of DMH on the content and diurnal rhythms of neurotransmitters in the hypothalamic structures under study is due to its affecting activities of the enzymes of biogenic amines synthesis, synaptic transmission, melatonin synthesis and secretion rhythms. The change in ROS formation that is caused by administration of DMH is likely to be due to a disturbance of diurnal rhythms of neurotransmitters that are one of the sources of formation of free radicals in the brain....

Read abstract  Full text PDF