Galactose oxidase: molecular analysis and mutagenesis studies.
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Amino Acid Sequence↗
Biomedical subjects
N Ito
Publications and source records attributed to N Ito.
Subchronic oral toxicity study of captafol in B6C3F1 mice.
The effects of subchronic administration of captafol were studied in B6C3F1 mice given dose levels of 0, 0.3, 0.625, and 1.25% in the diet for 12 wk. There was a dose-related decrease in body weight gain during the 12-wk experiment and a loss of body weight in the 1.25% group of both sexes. Whiles the mice given captafol consumed less diet than the control mice, this was not directly dose-related. The relative weights of liver demonstrated a tendency for dose-dependent increase. Light-microscopic examination revealed cytoplasmic vacuolar degeneration, depending in severity on the dosage, in the livers of both sexes given captafol. In conclusion, the findings obtained from the present subchronic toxicity study indicated the liver to be a primary target organ.
Administration, Oral↗
The role of premotor cortex and the supplementary motor area in the temporal control of movement in man.
In the present study temporal control of movement was systematically analysed in patients with unilateral lesions of the lateral or medial premotor cortex (PMC) or supplementary motor area (SMA) and in age-matched controls. The ability to learn new temporal adjustments was evaluated by examining rhythm reproduction using either the left or right hand or both hands in an alternating manner. A severe impairment in rhythm reproduction was found after lateral or medial PMC lesions; the deficit was most pronounced when our patients were required to use both hands in an alternating manner. The impairment occurred in the absence of difficulties in manual dexterity or impairments in discriminating the rhythm patterns. In a second series of experiments the contribution of the SMA in organizing movements in the time domain was examined. In this series, two patients with left-sided lesions, including the SMA but sparing tissue from the lateral hemispheric surface, and seven age-matched controls were requested to reproduce rhythm constellations in the presence of a sound signal and from memory. Results reveal that patients with left medial lesions involving the SMA had most severe difficulties to produce any rhythms from memory, though they were able to produce the rhythms under auditory pacing. This deficit in programming sequential patterns from memory in the time domain should be interpreted in the context of a decline in the ability to benefit from previous stimulus presentation, which prevents an effective later programming of these sequences when they have to be rehearsed from memory. It was found that patients with left SMA lesions had an increase in reaction time on a sequential digit task when sequences had to be produced under delayed conditions; by contrast, the controls showed a decrease of reaction time after previous stimulus presentation. The present findings extend previous knowledge on sequential motor tasks and argue for a critical role for both the SMA and the premotor cortex in the generation of sequences from memory that fit into a precise timing plan.
Adult↗
Modification of carcinogenesis by alpha-tocopherol, t-butylhydroquinone, propyl gallate and butylated hydroxytoluene in a rat multi-organ carcinogenesis model.
Effects of the dietary antioxidants alpha-tocopherol (alpha-Toc), t-butylhydroquinone (TBHQ), propyl gallate (PG) and butylated hydroxytoluene (BHT) were examined using a multi-organ carcinogenesis model. Groups of 20 F344 male rats were treated with a single intragastric administration of 100 mg/kg body weight N-methyl-N'-nitro-N-nitrosoguanidine, a single intragastric administration of 750 mg/kg body weight N-ethyl-N-hydroxyethylnitrosamine, two subcutaneous injections of 0.5 mg/kg body weight N-methylbenzyl-nitrosamine and four subcutaneous injections of 40 mg/kg body weight 1,2-dimethylhydrazine. At the same time the rats were given 0.1% N-dibutylnitrosamine for 4 weeks and then 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine for 2 weeks in the drinking water, for a total carcinogen exposure period of 6 weeks. Starting 3 days thereafter the rats received 1% alpha-Toc, 1% TBHQ, 1% PG or 0.7% BHT in the diet, or basal diet alone. Further groups of 10-15 animals each were treated with antioxidant alone or basal diet alone as controls. Surviving animals were killed at the end of week 36. Histopathological examination showed that alpha-Toc increased the incidence of glandular stomach atypical foci but reduced the incidence and multiplicity of kidney atypical tubules. TBHQ significantly elevated the incidences of esophageal papillary or nodular (PN) hyperplasias and papillomas, as well as forestomach papillomas, but significantly decreased the multiplicity of colon adenocarcinomas. PG was only effective in reducing the multiplicity of kidney atypical tubules. BHT enhanced the development of thyroid hyperplasias, but strongly reduced the incidence and multiplicity of colon adenocarcinomas. This compound was also associated with lowered incidence and multiplicity of renal cell tumors. None of the agents studied was unequivocal in exerting either positive or negative influence.
1,2-Dimethylhydrazine↗
Promotion of cholangiocarcinogenesis in the hamster liver by bile duct ligation after dimethylnitrosamine initiation.
Administration of hepatocarcinogenic nitrosamines before or after infection with the liver fluke, Opisthorchis viverrini (OV), results in marked development of cholangiocellular and hepatocellular precancerous and cancerous lesions in the hamster liver. The promoting effects of OV are believed to be exerted either mechanically, chemically or immunologically. To test the influence of possible mechanical effects, Syrian hamsters were initiated with a single i.p. injection of dimethylnitrosamine (DMN) 20 mg/kg and subjected 2 weeks later either to a sham operation or to complete ligation of the extrahepatic bile duct to the left lateral lobe. At the end of week 40, the animals receiving DMN-initiation and ligation had a 60.9% incidence of cholangiofibrosis, 21.7% of mucous cystadenomas and 39.1% of cholangiocarcinomas, whereas the group given DMN alone only developed cholangiofibrosis, limited to 5% of the animals. In the latter case neither cystadenomas nor cholangiocarcinomas were observed. The incidence of hepatocellular nodules did not differ between the two groups and no tumorous lesions developed in either the ligated or the untreated groups without DMN pretreatment. Complete ligation of the bile duct itself led to a series of events; obstruction of bile flow being followed by dilatation, cyst formation, and necrosis of the bile duct epithelium and surrounding affected areas leading to regenerative proliferation. The results are in line with the conclusion that parasite-associated proliferation in target cell populations is, at least in part, responsible for the influence of OV on liver tumor development.
Animals↗
Dose-dependence of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) carcinogenicity in rats.
The dose-dependence of 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) carcinogenicity was investigated in F344 rats of both sexes administered the heterocyclic amine in the diet at concentrations of 25 or 100 p.p.m. for up to 104 weeks. Incidences of mammary adenocarcinomas were 7% (2/30) for 25 p.p.m. and 47% (14 of 30 rats) for 100 p.p.m. in females and those of colon adenocarcinomas were 43% (13/30) for males and 13% (4/30) for females of the 100 p.p.m. groups. No mammary adenocarcinomas were induced in males and no colon carcinomas were observed in the 25 p.p.m. groups of either sex. Furthermore, development of lymphocytic leukemia was apparently enhanced by PhIP in males. In a separate experiment, dose-dependent induction of aberrant crypts in the large intestine, considered as preneoplastic lesions, was evident after 8 weeks feeding of PhIP-supplemented diet at doses of 25, 100 or 400 p.p.m. Thus a clear dose-dependency was demonstrated for both colon and mammary carcinogenesis. Since PhIP is a particularly abundant heterocyclic amine and its carcinogenic organotropism overlaps with the types of neoplasias most commonly observed in western countries, the compound may be extremely important with respect to human cancer development.
Adenocarcinoma↗
Enhancing effect of concomitant L-ascorbic acid administration on BHA-induced forestomach carcinogenesis in rats.
The effects of the synthetic antioxidant butylated hydroxyanisole (BHA) and naturally occurring antioxidants such as L-ascorbic acid (AsA; vitamin C), citric acid, benzoic acid or gallic acid in combination, on the development of rat forestomach epithelial lesions were investigated. A dietary level of 2.0% was selected for all antioxidants and the experimental period was 1 year. As compared with BHA alone, treatment with AsA in combination with BHA increased the severity of the hyperplasia in the mid-region, but not in the prefundic region of the forestomach epithelium, as well as the multiplicity of forestomach tumors. Furthermore, incidences of squamous cell carcinomas (SCCs) in the forestomach were significantly elevated in this group, while papilloma development only showed a tendency to increase. In addition, SCC invasion into the muscle layer of the forestomach was observed only in the BHA + AsA group. Treatment with the other antioxidants did not affect BHA-induced forestomach lesion development. The present study demonstrated that AsA can clearly enhance BHA forestomach carcinogenesis.
Animals↗
Carcinogenicity of catechol in F344 rats and B6C3F1 mice.
Carcinogenicity of catechol, a naturally occurring and industrial chemical which has been shown to have strong cell proliferating potential on rat glandular stomach epithelium, was investigated in male and female F344 rats and B6C3F1 mice. Groups of 30 male and female F344 rats and B6C3F1 mice were treated with 0.8% catechol in powdered diet continuously for 104 weeks (rats) or 96 weeks (mice). At necropsy, neoplastic lesions were observed mainly in the glandular stomach of both species. Adenomas were found in all rats and in the majority of mice: 29 out of 30 (97%) in males and 21 out of 29 (72%) females. In addition 15 out of 28 (54%) and 12 out of 28 (43%) of the male and female rats respectively, had well differentiated adenocarcinomas. No adenocarcinomas were found in mice of either sex. In the forestomach epithelium, although significant increase in papilloma development was not evident, incidences of squamous cell hyperplasia were significantly increased in rats and mice of both sexes. In other organs examined, incidence and numbers of liver hyperplastic foci per cm2 liver section were significantly lower in male rats. Although the incidence was not different, the numbers of hyperplastic foci were also significantly reduced in female rats. Thus the present experiment clearly demonstrated that catechol exerts carcinogenic activity in rodent glandular stomach epithelium.
Adenocarcinoma↗
Modification of BHA forestomach carcinogenesis in rats: inhibition by diethylmaleate or indomethacin and enhancement by a retinoid.
The long-term effects of butylated hydroxyanisole (BHA), in combination with various other chemicals on the development of forestomach lesions in rats were investigated. BHA is a synthetic antioxidant, and the other agents included the glutathione-depleting agent diethylmaleate (DEM), the anti-inflammatory drugs indomethacin (IM), dexamethazone (DEX), 6-aminocaproic acetate (6-ACA) and FOY (gabexate mesilate), and the vitamin all-trans-retinol acetate (RA). Concurrent treatment with BHA (1% in diet) and DEM, IM, DEX or FOY for 52 weeks inhibited development of forestomach epithelial hyperplasia as compared to BHA alone, while simultaneous treatment with RA enhanced hyperplastic development. However, the inhibition by DEX or FOY was only partial and in the DEX case, in particular, might have been due to weight loss. Since the most effective inhibitory influence on BHA-induced forestomach lesions exerted in this 1-year experiment was by DEM, a further 2-year experiment was conducted to confirm whether DEM actually can exert inhibitory effects on BHA (2% in diet)-induced forestomach carcinogenesis. The results demonstrated that induction of forestomach hyperplasias and papillomas by BHA was significantly reduced by combination treatment with DEM. Both multiplicity and incidence of forestomach papillomas were significantly decreased, while squamous cell carcinoma development showed a tendency for decrease only.
Animals↗
Effects of green tea catechins in a rat multi-organ carcinogenesis model.
The effects of dietary administration of green tea catechins (GTC) were examined using a multi-organ carcinogenesis model. Groups of 15 F344 male rats were initially treated with a single i.p. administration of 100 mg/kg body wt N-diethyl-nitrosamine, 4 i.p. administrations of 20 mg/kg body wt N-methylnitrosourea, 4 s.c. doses of 40 mg/kg body wt 1,2-dimethylhydrazine, together with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine for 2 weeks and then 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine for 2 weeks, both in the drinking water, for a total initiation period of 4 weeks. GTC in the diet, at doses of 1.0 or 0.1%, was administered from 1 day before and during carcinogen exposure, after carcinogen exposure or both during and after carcinogen exposure. Further groups of animals were treated with carcinogen, 1% GTC or basal diet alone as controls. All animals were killed at the end of week 36, and all major organs examined histopathologically. The numbers of small intestinal tumors (adenomas and carcinomas) per rat were significantly reduced in the groups treated with 1% GTC during (0.13 +/- 0.35) and after carcinogen exposure (0.31 +/- 0.48) and in those receiving 1% and 0.1% GTC both during and after carcinogen exposure (0.14 +/- 0.36, 0.46 +/- 0.97 respectively) as compared with the carcinogen alone group (1.07 +/- 1.21). On the other hand, numbers of glutathione S-transferase placental form positive liver foci per cm2 were slightly but significantly increased in the groups treated with 1 and 0.1% GTC during carcinogen exposure, 1% GTC after carcinogen exposure and 1% GTC both during and after carcinogen exposure. The results indicated that while GTC inhibits small intestinal carcinogenesis it slightly enhances hepatocarcinogenesis in a dose dependent manner when applied both during and after carcinogen exposure.
1,2-Dimethylhydrazine↗
Sensitive measurement of phase shifts due to the ac Stark effect in a Ca optical Ramsey interferometer.
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Journal Article↗
Strong inhibition of 2-amino-6-methyldipyrido[1,2-a:3',2'-d] imidazole-induced mutagenesis and hepatocarcinogenesis by 1-O-hexyl-2,3,5-trimethylhydroquinone.
The effects of 3-O-dodecylcarbomethylascorbic acid (3-O-DAsA), 3-O-ethylascorbic acid (3-O-EAsA) and 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ) on 2-amino-6-methyldipyrido[1,2-a:3',2'-d]-imidazole (Glu-P-1)-induced mutagenesis and hepatocarcinogenesis were examined. In a Salmonella assay, addition of 2.5 to 20.0 mg of HTHQ to Salmonella TA 98 in the presence of S-9 mixture dose-dependently inhibited Glu-P-1-induced mutagenesis. The highest dose showed a 99% reduction in revertants. 3-O-DAsA and 3-O-EAsA were without effect. In an animal study using the medium-term bioassay system for the detection of hepatocarcinogens or hepatopromoters in F344 male rats, treatment with Glu-P-1 alone was associated with a significant increase in the number and area of GST-P-positive foci (47.5 +/- 8.9 and 11.1 +/- 4.7, respectively). Combined treatment with 1.0% HTHQ significantly reduced the number and area of GST-P-positive foci (to 8.1 +/- 2.1 and 0.6 +/- 0.2) while 3-O-DAsA exerted marginal inhibition and 3-O-EAsA had no effect. On the other hand, all three of these compounds slightly enhanced the numbers and areas of foci when given alone. The results indicate that HTHQ is a potent chemopreventer of Glu-P-1-induced hepatocarcinogenesis.
Animals↗
Sequential observation of rat prostate lesion development induced by 3,2'-dimethyl-4-aminobiphenyl and testosterone.
3,2'-Dimethyl-4-aminobiphenyl (DMAB), when combined with high doses of testosterone propionate (TP) induces invasive adenocarcinomas with metastatic potential in the rat prostate. The processes underlying this tumor development, including the involvement of atypical hyperplasias, were sequentially investigated in F344 rats. DMAB was given subcutaneously at a dose of 50 mg/kg body weight 10 times at 2-week intervals. TP was administered chronically (in Silastic tubes) from the beginning of the experiment or after the DMAB administration until termination (week 60). Invasive adenocarcinomas were induced in the lateral and anterior prostate as well as the seminal vesicles. Atypical hyperplasias appeared from an early stage, with the later appearance of cancers being closely associated with such foci of morphological alteration. The findings confirm that combined administration of DMAB and pharmacological doses of TP yields invasive adenocarcinomas in the rat prostate and provide further support for the conclusion that atypical hyperplasias are premalignant lesions.
Aminobiphenyl Compounds↗
Enhancing effect of cadmium on rat ventral prostate carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl.
The effects of cadmium given at different stages during 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced rat prostate carcinogenesis were investigated using male F344 rats. Animals were given 10 subcutaneous injections of 50 mg/kg body weight of DMAB or the corn oil vehicle at two-week intervals. In addition, cadmium was administered at doses of 0, 10, or 30 mumol/kg body weight as single intramuscular injection on the 1st day of the experiment or one day after the last injection of DMAB at week 20. Two further groups were subjected to administration of cadmium at 10 mumol/kg at week 20 and then 5 mumol/kg at week 40, or 10 mumol/kg at week 20 and then 5 mumol/kg at weeks 30, 40 and 50. At the termination, 60 weeks after the beginning of the experiment, the incidences and multiplicity of ventral prostate carcinomas in the groups given cadmium plus DMAB demonstrated a consistent tendency for increase over control values (groups receiving DMAB or cadmium alone). The numbers of carcinomas per rat and per unit area of prostate section were significantly elevated in the two groups given low doses of cadmium after cessation of DMAB administration. Cadmium alone also induced a few prostate carcinomas. The influence on development of prostate tumors did not appear to be a result of the induced severe testicular atrophy because serum testosterone levels were not affected. The results indicate that cadmium and DMAB can act synergistically to cause rat prostate carcinogenesis.
Aminobiphenyl Compounds↗
Time-dependent modulation of liver lesion development in Opisthorchis-infected Syrian hamster by an antihelminthic drug, praziquantel.
In the North-east of Thailand, repeated antihelminthic therapy has been introduced for control of the opisthorchiasis known to be a major risk factor for cholangiocellular carcinomas. What influence this may have on tumorigenesis, however, remains unclear. The effects of administration of praziquantel, an antihelminthic drug, at different time points subsequent to infection with Opisthorchis viverrini (OV) on 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN)-initiated lesion development in the liver of female Syrian hamsters were therefore investigated. Praziquantel (250 mg/kg body weight, i.p.) was given 4, 12 or 20 weeks after infection of DHPN-treated animals (two 1000 mg/kg i.p. injections at weeks 0 and 2) with 60 OV metacercariae (at week 4). Survivors at week 38 were killed and examined. It was found that whereas praziquantel administration at the earlier two time points was effective at reducing hepatocellular nodule development, the results for cholangiocellular lesions were less pronounced, significant reduction only being evident in hamsters treated 4 weeks after parasite infestation. The findings thus indicate that enhancement of DHPN-initiated bile duct carcinogenesis by opisthorchiasis is both rapid and to a large degree irreversible. Hepatocellular lesion development in this model, on the other hand, appears to correlate more closely with the duration of parasite-associated proliferative stimulus.
Animals↗
Correlation between medium-term multi-organ carcinogenesis bioassay data and long-term observation results in rats.
The effects of four test chemicals [2-acetylaminofluorene (2-AAF), D,L-ethionine (ethionine), butylated hydroxyanisole (BHA), and catechol] were compared in medium- and long-term in vivo systems. In the medium-term assay, animals were sequentially treated with N-diethylnitrosamine (100 mg/kg body weight, i.p., single injection), N-methylnitrosourea (20 mg/kg body weight, i.p., 4 times during weeks 1 and 2), N-butyl-N-(4-hydroxybutyl)nitrosamine (0.05% in the drinking water during weeks 1 and 2), 1,2-dimethylhydrazine (40 mg/kg body weight, s.c., 4 times during weeks 3 and 4) and dihydroxy-di-N-propylnitrosamine (0.1% in the drinking water during weeks 3 and 4) for multi-organ initiation, and then treated with one of the four test chemicals for 24 weeks, and killed at week 28 (group 1). In the long-term assay, animals were treated in the same manner and then given basal diet and tap water (group 3) or test chemical continuously (group 4) for the remainder of the lifespan. Animals receiving multi-organ initiation and then maintained on basal diet for 24 weeks (group 2) or their lifespan (group 5) served as controls. Detailed histopathological examinations were performed on all rats. Hepatocellular carcinoma incidences in the long-term assay were found to reflect closely the respective medium-term results. Induction of proliferative forestomach or glandular stomach lesions by BHA and/or catechol, and bladder lesions by 2-AAF and BHA in the medium-term assay also correlated with tumor development in the long-term. Furthermore, inhibition of thyroid proliferative lesions by all test chemicals corresponded with low thyroid tumor incidences in the long-term assay. The observed strong correlation between medium- and long-term results confirms the applicability of our medium-term multi-organ carcinogenesis bioassay system for detection of modifying effects of test chemicals in different organs.
2-Acetylaminofluorene↗
Dicephalus, Arnold-Chiari malformation and spina bifida in a Japanese black calf.
A case of dicephalus, Arnold-Chiari malformation (ACM) and spina bifida was reported in a Japanese Black calf. Both brains and crania showed the same abnormalities as those of the monocephalic cases with ACM and were mirror-images of each other. The common findings were elongation of the brain, caudal displacement and hypoplasia of the cerebellum, dorso-ventral compression of the skull, platybasia, and enlargement of the foramen magnum. The craniolacunia was also found in our case.
Abnormalities, Severe Teratoid↗
Effects of high salt intake on control of hindlimb vascular resistance by arterial baroreflex and vagal afferents in spontaneously hypertensive rats.
1. This study aimed to examine whether a high salt diet alters control of vascular resistance by arterial baroreflex and vagal afferents in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). 2. SHR and WKY aged 8 weeks were fed either high (8%) or normal salt (0.4%) diet for 4 weeks. Arterial baroreflex control of hindlimb vascular resistance was assessed by examining reflex-induced vasodilation and vasoconstriction in response to phenylephrine and nitroprusside, respectively, in the constant-flow perfused hindlimb of urethane-anesthetized rats. 3. Tonic influence of the cardiopulmonary vagal afferents was evaluated by examining the effects of vagotomy on hindlimb vascular resistance and on the gain of arterial baroreflex control of hindlimb vascular resistance. 4. The gain of the arterial baroreflex control of hindlimb vascular resistance in response to both phenylephrine and nitroprusside were not significantly different between SHR receiving high and normal salt diets, and between WKY receiving high and normal salt diets. 5. Vagotomy increased hindlimb vascular resistance in all four groups of rats. However the high salt diet than those in SHR on a normal salt diet but similar between the two groups of WKY. Vagotomy increased the slope of arterial baroreflex control of hindlimb vascular resistance in SHR receiving a normal salt diet and the two groups of WKY but not in SHR receiving a high salt diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Afferent Pathways↗