The ecologic risk assessments consisting of hazard and exposure analysis are of prime importance for pesticide registration. In particular, the U.S.A.'s assessment on aquatic environment using simulation model is well organized. We introduce the current methods and ECOFRAM (Ecological Committee on FIFRA Risk Assessment Methods) by describing the case of pyrethroid insecticide as an example.
The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], functions to maintain calcium and phosphorus homeostasis and plays an important role in cell proliferation and differentiation. Since the discovery of non-classical functions of 1α,25(OH)2D3, many 1α,25(OH)2D3 analogs have been synthesized to separate calcemic properties from the antiproliferative cell-differentiating properties. 1α,25(OH)2D3 and its precursor, 25-hydroxyvitamin D3 [25(OH)D3], are metabolized via C-24 and C-23/26 oxidation pathways. Recently, a novel A-ring modification metabolic pathway of 1α,25(OH)2D3, the C-3 epimerization pathway, was identified. In our laboratory, C-3 epimerized metabolites of major natural vitamin D3 metabolites, 1α,25(OH)2D3, 25(OH)D3 and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], and a synthetic analog, 22-oxacalcitriol [22-oxa-1α,25(OH)2D3, OCT], were identified. In addition, other novel metabolites of OCT were assigned to two kinds of C-25 dehydrates, 25-dehydroxy-25-ene-22-oxa-1α-hydroxyvitamin D3 [25-ene-22-oxa-1α(OH)D3] and 25-dehydroxy-24-ene-22-oxa-1α-hydroxyvitamin D3 [24-ene-22-oxa-1α(OH)D3]. In this mini-review, the identification of C-3 epimers of vitamin D3 compounds and C-25 dehydrates of OCT using 1H-NMR and LC-MS techniques is described. Furthermore, the cell-specific generation and biological activity of these novel metabolites are reviewed.
Prion protein (PrP) exists in two different isoforms; a normal cellular isoform (PrPC) and an abnormal infectious isoform (PrPSc), the latter is a causative agent of prion disease such as Bovine Spongiform Encephalopathy (BSE, mad cow disease) and Creutzfeldt-Jakob disease (CJD). Great concern about variant CJD, which is caused by ingesting BSE-contaminated products, is also emerging and spreading over Japan since the first BSE-affected cattle was identified in September, 2001. The amino acid sequences of PrPC and PrPSc are identical, but their conformations are rather different; PrPC is rich in the non β-sheet isoform while PrPSc is rich in the β-sheet isoform. Our prion research focuses on further understanding such an unprecedented mechanism by identifying auxiliary factor(s) other than PrPC and PrPSc. These studies also help us to develop "therapeutics and prevention methods" for prion disease. Three major trials; genetic manipulation with dominant negative mutant PrPC gene working against a hypothetical host-specific factor, antibody therapy with anti-PrP antibodies which block PrPC-PrPSc binding, and PrPSc unfolding therapy with a novel-class molecular chaperone, are currently underway.
In recent years, cancer-related genes have been analyzed at the molecular level as predictive indicators for cancer therapy. Among those genes, the tumor suppressor gene p53 is worthy of notice in cancer therapy, because the p53 molecule prevents the malignant degeneration of non-cancer cells by regulating cell-cycle arrest, apoptosis, and DNA repair. An abnormality of the p53 gene introduces a genetic instability and increases the incidence of carcinogenesis and teratogenesis. Therefore, p53 is called a guardian of the genome. Mutations of p53 are observed at a high frequency in human tumors, and are recognized in about half of all malignant tumors in human head and neck cancers. We previously reported that radio- and heat-sensitivities of human cultured tongue squamous cell carcinoma cells are p53-dependent, and are closely correlated with the induction of apoptosis. In a human cell culture system, the interactive hyperthermic enhancement of radiosensitivity was observed in wild-type p53 cells, but not in mutated p53 cells. In a transplanted tumor system, the combination therapies of radiation and hyperthermia induced efficient tumor growth depression and apoptosis in the wild-type p53 tumors. In this review, we discuss the p53 activation signaling pathways through the modification of p53 molecules, such as phosphorylation after radiation and hyperthermia treatments.
Qigong is a method adopted by many people for their health maintenance and therapy at present. But up to this day, there is still no detailed conclusion as to the physiological state of Qigong or how to define it. This study tries to explore and provide a definition for Qigong state. The subject applied Neiyang Gong to enter Qigong state. We used a multifunctional physiological recorder to record the difference of various physiological parameters before and after entering Qigong state. The results showed that when the subject entered Qigong, the alpha brain wave at the left forehead of the cerebrum was concentrated. Temperature of the left palm rose extensively. There were large fluctuations in the electromyogram (EMG) base line of the left hand dorsum. Finger pulse amplitude (FPA) pulse appeared very frequent and the amplitude increased. Skin conductance level (SCL), increased evidently. These physiological parameter variations showed that the subject is under a certain emotional state. Also, exploration of the three characteristics of Qigong showed that Qigong should be a kind of emotional state: we can see that there were several kinds of reactionary methods in the behavioral reactions of Qigong, some people can enter Qigong state in an instant, and after having learnt certain methods and having entered Qigong state, it becomes easier to enter Qigong emotional state continuingly. By understanding the mechanical system of Qigong, we are able to develop a Qigong method that is more effective to physical health maintenance.
For the purpose of reliable identification of suxamethonium (SUX) use, the stability and adsorption of SUX and its specific hydrolysis product succinylmonocholine (SMC) were investigated under various storage conditions using liquid chromatography-electrospray ionization mass spectrometry (LC-ESI MS). Significant and slight adsorption to glassware was observed for SUX and SMC, respectively, whereas there was no significant adsorption to plasticware by either SUX or SMC. The silanization methods for glassware have also been found to affect the adsorption of SUX to glassware. Additionally, alkaline conditions led to significant loss of both SUX and SMC due to their hydrolysis, but SMC showed greater stability than SUX under the present storage conditions, suggesting that SMC is a superior marker for SUX use when stored in alkaline conditions. On the other hand, there was no significant loss of SUX and SMC under acidic conditions even in human urine at room temperature or higher (20-38°C), or in distilled water.
Cytotoxicities of propranolol (PL) and its active metabolite, 4-hydroxypropranolol (4-OH-PL), were examined in a human hepatoma cell line, Hep G2. Hep G2 cells were cultured in the presence of β-naphthoflavone (BNF, 25 or 50 μM), lansoprazole (LPZ, 25 or 50 μM) or 0.5% dimethylsulfoxide (vehicle) for 48 hr. The cells were harvested, and microsomal and cytosolic fractions were prepared by differential centrifugation methods. Various enzyme activities were determined as follows: microsomal 7-ethoxyresorufin (ER) O-deethylation as a CYP1A1 index, microsomal phenacetin (PN) O-deethylation as a CYP1A2 index, microsomal and cytosolic p-nitrophenyl acetate (NPA) hydrolysis as a carboxylesterase index and cytosolic 4-OH-PL sulfation as a sulfotransferase index. The pretreatment of Hep G2 cells with LPZ or BNF increased microsomal ER O-deethylase activities, and the potency of BNF was much higher than that of LPZ. Cytosolic 4-OH-PL sulfation was also elevated by the pretreatment with BNF but not with LPZ. Microsomal PN O-deethylase activity was not detectable in either the control or BNF-pretreated group under the conditions used. Microsomal and cytosolic NPA hydrolase activities were similar between the control and the BNF-pretreated groups. Cytotoxicities of PL and 4-OH-PL were attenuated in BNF-pretreated Hep G2 cells compared to non-pretreated Hep G2 cells. These results suggest that increased activities of microsomal CYP1A1 and cytosolic sulfotransferases by pretreatment with BNF may contribute to the attenuating the cytotoxicity of PL and 4-OH-PL in Hep G2 cells, at least in part.
In this study, liver microsome-mediated activation of diphenyl (DP), diphenylmethane (DPM) and 2,2-diphenylpropane (DPP) to estrogens was demonstrated. These three compounds were negative in estrogen reporter assay using estrogen-responsive human breast cancer cell line MCF-7. However, they exhibited estrogenic activity after incubation with liver microsomes of 3-methylcholanthrene-treated rats in the cases of DP and DPM, or of phenobarbital-treated rats in the cases of DP and DPP, in the presence of NADPH. When these compounds were incubated with liver microsomes in the presence of NADPH, monohydroxyl and dihydroxyl derivatives were formed. These hydroxylated metabolites, 4-hydroxydiphenyl, 3-hydroxydiphenyl, 2-hydroxydiphenyl, 4-hydroxydiphenylmethane, 2-(4-hydroxyphenyl)-2-phenylpropane (4-OH-DPP), 4,4′-dihydroxydiphenyl, 4,4′-dihydroxydiphenylmethane and 2,2-bis(4-hydroxyphenyl)propane (bisphenol A), all exhibited estrogenic activity in MCF-7 cells. Binding assay of these hydroxylated compounds with rat uterus estrogen receptor was also positive. These results suggest that the estrogenic activities of DP, DPM and DPP were due to the formation of hydroxylated metabolites by the liver cytochrome P450 system.
A new testing method for the assessment of hazardous environmental chemicals using cultured human neuronal cells has been developed. This method is based on the image analysis of the neurite extension in human neuroblastoma NB-1 cells: the length of the extended neurites was determined using image analysis software. Using this system, 255 chemicals including methylmercury and endocrine disrupting chemicals were tested. Methylmercury and several chemicals inhibited neurite extension, while cadmium chloride, phthalates, and many other chemicals promoted it. These results suggest that the extended neurite length is a useful biological marker for the effects of neurotoxic environmental chemicals, especially on the developing nervous system.
Resistance to the toxicity of cadmium (Cd) was examined in male Wistar-Imamichi (Wistar-IM) and Fischer 344 (Fischer) rats. The Wistar-IM strain was confirmed to exhibit strong resistance compared to the Fischer strain. The resistance in first filial (F1) males was intermediate between that in Wistar-IM and that in Fischer males. The data from reciprocal crosses indicate that the strong resistance to Cd toxicity in male Wistar-IM rats is autosomal and inherited as an incompletely dominant phenotype.
Bisphenol A (BPA) is a common environmental endocrine disruptor and BPA sulfate has been demonstrated as one of metabolites of BPA. Since it has been observed to have effects on the central nervous system (CNS), we examined the effects of sulfoconjugation on the toxicity of BPA in a human neuroblastoma cell line, NB-1. NB-1 cells showed limited but significant sulfotransferase activity toward BPA in vitro (Km = 74 μM, Vmax = 7.8 pmol/min/mg). Accumulation of BPA sulfate was observed for 12 hr to 4 days after 10 μM BPA was added to a culture of NB-1 cells. These results suggest that BPA is partly detoxified by the sulfoconjugation reaction in human neuronal cells.
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