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K Hakoi

Publications and source records attributed to K Hakoi.

At least 19 recordsLinked to original sources
PubMed1996

Medium-term bioassay for the hepatocarcinogenicity of hexachlorobenzene.

Hexachlorobenzene (HCB) is an important environmental contaminant derived mainly from industrial and agricultural sources. It is carcinogenic in mice, rats and hamsters. It has now been studied in a medium-term bioassay for carcinogenicity based on the induction of preneoplastic lesions in the liver. We report here that the bioassay can rapidly detect carcinogenic doses of HCB and that there is a clear dose-response relationship. At the lowest dose of HCB administered, the incidence of preneoplastic lesions in the liver was no different from that in controls.

Animals↗
PubMed1996

[A 26-week oral repeated dose toxicity study of a new antineoplastic agent S-1 in rats].

S-1 was administered to male and female rats by gavage for 26 weeks at 0, 1, 5, and 10 mg/kg/day followed by 5-week recovery period for the control, 5, and 10 mg/kg/day groups. Treatment at 5 or 10 mg/kg/day in both sexes produced keratosis of the tail, palm or sole. Weight gain and average food consumption were lowered by the treatment. Urine showed increases in protein and epithelial or white blood cells and a decrease in specific gravity. The blood showed decreases in red blood cell count, hemoglobin, and hematocrit as well as increases in MCH, platelet count, fibrinogen, and MCV. A/G ratio, albumin, and chloride were decreased while total cholesterol, free cholesterol, triglycerides, and phospholipids were increased. Histopathologically, treatment-related changes at 5 and 10 mg/kg/day were observed mainly in the lymphoid tissues and kidneys. Those changes included atrophy in the lymphoid tissues and chronic nephropathy-like changes in the kidneys. Other changes in the 10 mg/ kg/day group, included acanthosis and/or inflammation in the epidermis of the tail, sole, or palm, degeneration and disarrangement of ameloblasts, and atrophy of the testes. In a recovery study, although some changes in the sole, palm, or tail, and the kidneys remained, they were less extensive than they had been at the end of the treatment period. Based upon these observations, the non-toxic dose level was estimated to be 1 mg/kg/day (2.3 mg/kg/day, as the summed doses of tegafur, CDHP, and Oxo) in both sexes.

Administration, Oral↗
PubMed1995

Cell proliferation and advancement of hepatocarcinogenesis in the rat are associated with a decrease in connexin 32 expression.

The expression of connexin 32 (Cx32), a major liver gap junction protein, after partial hepatectomy (PH) and during development and progression of hepatocarcinogenesis was studied in the rat. Cx32 was quantitatively analyzed by counting immunohistochemically demonstrated protein spots on the membranes of hepatocytes. Livers were sequentially examined after PH to assess the correlation with cell proliferation. For the analysis of different stages in carcinogenesis, Cx32 was assayed in N-ethyl-N-hydroxyethylnitrosamine-induced enzyme altered foci (EAF), hyperplastic nodules (HN), hepatocellular carcinomas (HCC), pulmonary metastatic HCC and transplanted HCC in relation to their degree of altered enzyme expression. Cx32 showed: (i) a rapid decrease after PH to its lowest levels during and 12 h after the S phase of cell proliferation when 5-bromo-2'-deoxyuridine (BrdU) labeling indices were examined; (ii) a progressive decrease from early preneoplasia EAF to HN and HCC, values for pulmonary metastatic and transplanted HCC being 0; (iii) clearly inverse correlations with increased BrdU index and degree of altered enzyme expression in HN, indicating that these, with the lowest Cx32 count, are closest to HCC. Therefore, the observed decrease appears linked to cell proliferation and progression of hepatocarcinogenesis, providing a reflection of cellular independence and growth advantage.

Animals↗
PubMed1994

Modification of N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated urinary bladder carcinogenesis in rats by phytic acid and its salts.

The effects of dietary phytic acid and its salts on the promotion stage of two-stage urinary bladder carcinogenesis were examined. Male F344 rats were initiated by exposure to 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 wk, and then treated with basal diet containing a 2% supplement of phytic acid (PA), phytic acid dodecasodium salt (Na-PA), phytic acid dodecapotassium salt (K-PA), phytic acid hexamagnesium salt n-hydrate (Mg-PA) or no added chemical for 32 wk. Na-PA significantly increased the development of preneoplastic and neoplastic lesions of the urinary bladder. K-PA also brought about a tendency for increase in papillomas, whereas Mg-PA and PA were without effect. Both Na-PA and K-PA caused elevation of urinary pH, and Na+ or K+ concentration, respectively. These results confirm the promoting activity of the sodium salt of phytic acid for urinary bladder carcinogenesis and indicate modulation by urinary components, as demonstrated by increases in urinary pH, and Na+ concentration.

Animals↗
PubMed1993

Enhancement by non-mutagenic pesticides of GST-P positive hepatic foci development initiated with diethylnitrosamine in the rat.

The potential hepatocarcinogenicity of seven pesticides was examined using a rapid bioassay based on the induction of glutathione S-transferase placental form positive foci in the rat liver. Rats were initially injected with diethylnitrosamine and two weeks later were fed on diet supplemented with one of the pesticides for 6 weeks and then killed; all rats were subjected to a partial hepatectomy at week 3. Positive results were seen with chlorobenzilate (2000 ppm), vinclozolin (2000 ppm), malathion (4000 ppm), tecnazene (2000 ppm) and isoproturon (2000 ppm). S,S,S-tributylphosphorotrithioate (DEF, 200 ppm) and dicloran (2000 ppm) were negative in both number and area analyses. Although chlorobenzilate is carcinogenic in mice, malathion and vinclozolin have been reported as non-carcinogens in both rats and mice. Since the present system is based on the two-stage carcinogenesis hypothesis, it is possible that the chemicals showing positive results in this system possess at least tumor-promoting activity in the rat liver. This is very significant, as most carcinogens show tumor-promoting activity in their target organs.

Animals↗
PubMed1993

Carcinogenic potential of some pesticides in a medium-term multi-organ bioassay in rats.

The carcinogenic potential of 5 pesticides was analyzed using a medium-term multi-organ bioassay for carcinogenicity. Male F344 rats were initially treated with 3 known carcinogens (diethylnitrosamine, N-methyl-N-nitrosourea and N-bis(2-hydroxypropyl)nitrosamine) during a period of 4 weeks to induce neoplastic changes in a variety of organs, and then given one of 5 pesticides in the diet for a further 16 weeks. Neoplastic and pre-neoplastic lesions were found in the thyroid, kidney and urinary bladder with propineb, in the forestomach, kidney and thyroid with captan and folpet. The number of glutathione S-transferase placental-form-positive liver-cell foci was significantly increased in the captan- and phosmet-treated groups. Based on these findings, captan and propineb can be considered as carcinogens and carcinogenicity is suspected for folpet and phosmet. These results are in concordance with reported long-term carcinogenicity for captan, folpet and propineb. Daminozide was considered not to be carcinogenic. Thus, the present assay of 20 weeks' duration is useful for the prediction of potential carcinogens.

Animals↗
PubMed1993

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↗
PubMed1993

Comparison of reversibility of rat forestomach lesions induced by genotoxic and non-genotoxic carcinogens.

Reversibility of forestomach lesions induced by genotoxic and non-genotoxic carcinogens was compared histopathologically. Groups of 30 to 33 male F344 rats were given dietary 0.1% 8-nitroquinoline, dietary 0.4-0.2% 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, an intragastric dose of 20 mg/kg body weight N-methyl-N'-nitro-N-nitrosoguanidine once a week, or 20 ppm N-methylnitrosourethane in the drinking water as a genotoxic carcinogen, or 2% butylated hydroxyanisole, 2% caffeic acid, 2% sesamol or 2% 4-methoxyphenol in the diet as a non-genotoxic carcinogen for 24 weeks. Ten or 11 rats in each group were killed at week 24. Half of the remainder were maintained on basal diet alone for an additional 24 weeks and the other half were given the same chemical for 48 weeks, and then killed. Forestomach lesions induced by genotoxic carcinogens did not regress after removal of carcinogens. In contrast, simple or papillary hyperplasia (SPH), but not basal cell hyperplasia (BCH), induced by non-genotoxic carcinogens clearly regressed after cessation of insult. SPH labeling indices in the non-genotoxic carcinogen-treated cases decreased after removal of the carcinogenic stimulus whereas BCH values were low irrespective of treatment. Atypical hyperplasia (AH), observed at high incidences in rats treated with genotoxic carcinogens, was also evident in animals receiving non-genotoxic agents, even after their withdrawal, albeit at low incidences. AH labeling indices remained high even without continued insult. These results indicate that even with non-genotoxic carcinogens, heritable alterations at the DNA level could occur during strong cell proliferation and result in AH development. This putative preneoplastic lesion might then progress to produce carcinomas.

Animals↗
PubMed1993

Number of simultaneously expressed enzyme alterations correlates with progression of N-ethyl-N-hydroxyethylnitrosamine-induced hepatocarcinogenesis in rats.

Preneoplastic and neoplastic liver cell lesions, induced by EHEN (N-ethyl-N-hydroxyethylnitrosamine) in rats, were investigated to establish the numbers of simultaneously expressed altered enzyme phenotypes within the lesion cells. The lesions were divided into 5 classes on the basis of altered expression in one or more of the following 5 enzymes: glutathione S-transferase placental form, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, adenosine triphosphatase, and gamma-glutamyl transpeptidase. Class 1 lesions contained cells expressing one altered enzyme. Similarly, class 2, 3, 4 and 5 lesions had cells simultaneously expressing 2, 3, 4, and 5 enzyme alterations, respectively. Four histopathological categories of lesions, ACF (altered cell foci) (274 lesions), HN (hyperplastic nodules) (47 lesions), HCC (hepatocellular carcinomas) (99 lesions) and THC (transplanted hepatocellular carcinomas) (5 lesions) were studied. Proliferation potential was assessed in terms of 5-bromo-2'-deoxyuridine (BrdU) incorporation. The distribution profiles of classes 1 to 5 showed a clear reciprocal change from low class (1 to 2 enzymes) predominance in ACF to high class (4 to 5 enzymes) predominance in HN. Increase of BrdU labeling indices was clearly correlated with progression from HN to HCC. Only a small population of class 5 ACF showed a high BrdU labeling index, indicating particular potential for further development. Thus, the stages of EHEN-induced neoplasia were found to be characterized by gradual increase in the number of altered enzyme phenotypes, with acquisition of proliferative potential being associated with further progression towards malignant conversion.

Adenosine Triphosphatases↗
PubMed1992

Analysis of carcinogenic activity of some pesticides in a medium-term liver bioassay in the rat.

Eight pesticides were tested in a medium-term bioassay based upon the induction of preneoplastic lesions in the liver. Rats were initially given diethylnitrosamine intraperitoneally at a dose of 200 mg/kg body weight and 2 weeks later were treated with the pesticides for 6 weeks and then killed; all rats had a partial hepatectomy at week 3. Hepatocarcinogenic potential was assessed by comparing the number and area of glutathione S-transferase placental form positive foci in the liver with those of controls given diethylnitrosamine (DEN) alone. Positive results were seen with p,p-DDT and Triadimefon. Permethrin (mixture of 39% cis form and 61% trans form) showed borderline results. Permethrin (25/75), Deltamethrin, Cypermethrin (52/48), while Trimorphamide and Propineb gave negative results. Our findings provide experimental evidence to indicate that compounds active in this assay have a potential for liver carcinogenicity in rodents.

Animals↗
PubMed1992

Enhancing effects of diallyl sulfide on hepatocarcinogenesis and inhibitory actions of the related diallyl disulfide on colon and renal carcinogenesis in rats.

It has been reported that diallyl sulfide (DS) and diallyl disulfide (DDS), major volatile compounds in garlic (Allium sativum), exert anticarcinogenic activity in several organs in rodents. The modifying effects of these two chemicals were therefore assessed using two-step liver and multi-organ carcinogenesis models. In experiment 1, male F344 rats were given a single i.p. injection of N-diethylnitrosamine (200 mg/kg body wt) and then received DS or DDS by intragastric intubation at doses of 200 and 50 mg/kg body wt, respectively, three times a week for 6 weeks. All rats were subjected to two-thirds partial hepatectomy at experimental week 3. In experiment 2, male F344 rats were sequentially treated with five carcinogens with different organ target sites for 4 weeks, and then administered DS or DDS as in experiment 1 for 24 weeks. DS demonstrated clear enhancing effects on the development of glutathione S-transferase placental form positive foci in both experiments. On the other hand, an inhibitory potential in colon and renal carcinogenesis was observed in rats treated with DDS. Therefore, while DDS may act as a chemopreventive agent, DS may promote hepatocarcinogenesis.

Allyl Compounds↗
PubMed1992

Effects of modifying agents on conformity of enzyme phenotype and proliferative potential in focal preneoplastic and neoplastic liver cell lesions in rats.

Development of preneoplastic lesions in the rat liver under the influence of various modifiers was investigated with particular attention to changes in simultaneous expression of altered enzyme phenotype within the lesions (conformity) and proliferation potential. Degree of conformity of marker enzymes such as glutathione S-transferase placental form (GST-P), glucose-6-phosphate dehydrogenase (G6PD), glucose-6-phosphatase, adenosine triphosphatase and gamma-glutamyltranspeptidase was compared with levels of 5-bromo-2-deoxyuridine labeling. After initiation with diethylnitrosamine, rats were administered the hepatopromoter sodium phenobarbital (PB, 0.05%), the antioxidant ethoxyquin (EQ, 0.5%), or a peroxisome proliferator, clofibrate (CF, 1.0%) or di(2-ethylhexyl)-phthalate (0.3%) and killed at week 16 or 32. The PB promoting regimen was clearly associated with increase in the numbers of high conformity class lesions simultaneously expressing three to five enzymes, and elevated proliferation potential. The inhibitor, EQ, in contrast, brought about a time-dependent decrease in conformity so that only 1 or 2 alterations were most commonly observed at week 32. Lesion populations in the peroxisome proliferator- and especially CF-treated cases were characterized by obvious dissociation between degree of conformity and proliferative status. Such treatment-dependent differences were not always correlated with the size of the lesion. The results thus suggested that the conformity and proliferation potential of preneoplastic lesions are dependent on modification treatment. Overall, GST-P was found to be the most reliable marker, although G6PD was less influenced in the peroxisome proliferator cases.

Adenosine Triphosphatases↗
PubMed1991

A rapid in vivo bioassay for the carcinogenicity of pesticides.

Eight pesticides were tested in a bioassay based on the induction of preneoplastic lesions in the liver. Rats were given diethylnitrosamine intraperitoneally at 200 mg/kg bw and two weeks later were treated with pesticides for six weeks and then killed; all rats had a partial hepatectomy at week 3. Hepatocarcinogenic potential was assessed by comparing the number and area of glutathione s-transferase (placental form) -positive foci in the liver with those of controls given diethylnitrosamine alone. Positive results were seen with Chinomethionat, Phosmet and Propiconazole; the results obtained with Captan and Prochloraz were borderline; Benomyl, Daminozide and Folpet gave negative results. Our findings provide enough experimental evidence to indicate that great care should be exercised in the use of these compounds.

Animals↗
PubMed1991

Enhancement of GST-P positive liver cell foci development by combined treatment of rats with five heterocyclic amines at low doses.

Potential synergism between five heterocyclic amines at low doses was evaluated in a medium-term liver bioassay system for carcinogens. F344 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and then received test compound(s) in their diet for 6 weeks beginning 2 weeks later. Control groups received DEN or test compound(s) alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Compounds tested and reported positive were 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1, 150 p.p.m.), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2, 500 p.p.m), 2-amino-3-methylimidazo[4,5-f]quinoline (MeIQ, 300 p.p.m.), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, 400 p.p.m.). Groups were given each chemical at the carcinogenic dose, or 1/5 or 1/25 of this. Other groups received the five chemicals in combination, each at the 1/5 or 1/25 levels. Enhancing activity was assessed by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, the numbers being significantly increased with all chemicals at the highest dose. Trp-P-1, IQ and MeIQ also exerted positive influence even at the 1/5 dose level. Similar results were obtained regarding areas of foci at the highest dose levels, with the exception of Glu-P-2. An increase was also observed for MeIQ at the 1/5 dose. Additive or synergistic effects between the chemicals were evident in the groups given the five chemicals together at both the 1/5 and 1/25 dose levels, development of GST-P positive foic being increased over the sum totals of individual data for the 1/5 or 1/25 dose groups. Thus, carcinogenicity was predicted for all five heterocyclic amines tested in dose-dependent manner in the present system of 8 weeks duration, synergistic effects being apparent especially at the low dose level.

Animals↗
PubMed1991

Synergistic enhancement of thyroid tumor induction by 2,4-diaminoanisole sulfate, N,N'-diethylthiourea and 4,4'-thiodianiline in male F344 rats.

Three thyroid carcinogens, 2,4-diaminoanisole sulfate (DAAS), N,N'-diethylthiourea (DETU) and 4,4'-thiodianiline (TDA), were simultaneously administered in the diet to male F344 rats at one-third the concentration of the reported TD50 levels (610, 200 and 46 p.p.m. respectively) for 52 weeks. The resultant incidence of thyroid adenocarcinomas in the combined treatment group (18/18: 100%) was significantly higher than those in each individual treatment group (DAAS, 0/21; DETU, 1/21; TDA, 2/20). Hepatocellular carcinomas (9/18, 50%) and lung adenomas (6/18, 33%) were also induced by the combined treatment, the incidences being higher than in the TDA group (3/20, 15% and 4/20, 20% respectively) to which these tumors were limited in the three groups treated with single chemicals. Thus, the results indicated that the three carcinogens exert apparent synergism in thyroid carcinogenesis when administered simultaneously.

Aniline Compounds↗
PubMed1991

Promotion of rat hepatocarcinogenesis by praziquantel.

Praziquantel, the widely used anti-helminthic agent, was investigated for hepatocarcinogenesis-promoting potential using a medium-term liver bioassay system for carcinogens. F344 male rats were given a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg) and then starting 2 weeks later, received praziquantel in the diet at concentrations of 1.5 or 0.5%, or intragastrically at a dose of 1,500 mg/kg once a week for 6 weeks. Control groups received DEN or praziquantel alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Development of glutathione S-transferase placental form-positive foci in the liver was significantly increased in terms of both number and area with the 1.5% dose, while only area was affected by the 0.5% dose. The results thus indicate that praziquantel at high dose has promoting potential in rat hepatocytic tumorigenesis.

Alanine Transaminase↗