Relationship between cellular ATP content and cellular functions of primary cultured rat hepatocytes in hypoxia

The importance of oxygen in maintaining the functional integrity of hepatocytes has been well established in a variety of experimental models, such as in vivo , perfused liver and isolated hepatocytes. However, one of the shortcomings of these systems is their short life span. Therefore, we have examined the effects of long-term hypoxia on cellular adenine nucleotide content and cellular functions, such as albumin production, urea production and DNA synthesis, in adult rat hepatocytes in primary culture. Hepatocytes were cultured at a density of 11 × 10⁴ and 5 × 10⁴ cells/0.18 mL per cm² for the study of albumin and urea production and DNA synthesis, respectively, at various oxygen tensions (20, 12, 8 and 5%) for 24 h. Cellular ATP content in cultured hepatocytes in hypoxia gradually declined, corresponding to the decrease in oxygen tension, and the cellular ATP level at 5% oxygen was approximately 20% of that at 20% oxygen. Albumin production also decreased in parallel with the decrease in cellular ATP content in cultured hepatocytes in hypoxia. However, even when cellular ATP content gradually declined corresponding with the decrease in oxygen tension in cultured hepatocytes in hypoxia, such as at 8 or 5% oxygen, urea production remained at a high level; in contrast, DNA synthesis was completely suppressed. These results suggest that the cellular ATP content decreases in cultured hepatocytes during long-term hypoxia in relation to oxygen tension and that the relationship between decreased ATP levels and liver function in cultured hepatocytes during hypoxia differs for albumin production, urea production and DNA synthesis.     

Pharmacokinetic Analysis of Increased Toxicity of 2-sec-Butylphenyl Methylcarbamate (BPMC) by Fenitrothion Pretreatment in Mice

Pharmacokinetk Analysis of Increased Toxicity of 2-sec-ButylphenylMethylcarbamate (BPMC) by Fenitrothion Pretreatment in Mice.TSUDA, S., MIYAOKA, T., IWASAKI, M., AND SHIRASU, Y. (1984).Fundam. Appl. Toxicol. 4, 724–730. The potentiating effectof O,O-dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate(fenitrothion) on the toxicity of 2-sec-butylphenyl methylcarbamate(BPMC) in male mice was analyzed pharmacokinetically. The animalspretreated by dietary administration of 1000 ppm fenitrothionfor 1 week (4.4% of the po LD50 daily) did not show toxic symptomsexcept for a slight decrease in body weight In the fenitrothion-pretreatedmice, toxicity of fenitrothion was not changed but a fivefoldpotentiation was observed in po and ip acute lethality and athreefold potentiation of iv lethality of BPMC. Toxic signsafter BPMC administration were similar regardless of fenitrothionpretreatment or of route of administration. Fenitrothion pretreatmentfollowed by BPMC administration (20 mg/kg po or 8 mg/kg iv,approximate LD5 in the pretreated mice) significantly increasedthe plasma BPMC concentration and the total area under the plasmaconcentration versus time curve (AUG_0-. The pretreatment increasedthe oral AUC_0-, more greatly than the iv AUC_0-, (for po, 6.3-fold;for iv, 2.0-fold). The oral systemic availability of BPMC (fractionreaching systemic circulation) was increased by fenitrothiontreatment to 3.3-fold. These results suggest that a major causeof the potentiation may be the increase in amount of BPMC inthe systemic circulation.     

Differences in the Mode of Lethality Produced through Intravenous and Oral Administration of Organophosphorus Insecticides in Rats

Differences in the Mode of Lethality Produced through Intravenousand Oral Administration of Organophosphorus Insecticides inRats. TAKAHASHI, H., KOJIMA, T., IKEDA, T., TSUDA, S. and SHIRASU,Y. (1991). Fundam. Appl. Toxicol. 16, 459–468. This studywas undertaken to investigate the possibility that mechanismsother than cholinesterase (ChE) inhibition account for the acutetoxicity of organophosphorus insecticide. Both the PO type insecticide(direct ChE inhibitors: chlorfenvinphos and dichlorvos) andthe PS type insecticide (indirect ChE inhibitors: diazinon andfenthion) were employed. Rats treated with lethal doses of intravenousand oral PO type insecticides and oral PS type insecticidesexhibited typical signs of anti-ChE poisoning along with markedinhibition of brain and erythrocyte ChE activity. In contrast,rats given lethal doses of intravenous PS type insecticidesexhibited tonic convulsions and opisthotonos, with only slightinhibition of ChE activities. When PO type insecticides wereintravenously administered to anesthetized and conscious rats,animals exhibited typical anti-ChE poisoning signs in cardiorespiration:hypertension and apnea which were antagonized by atropine. Afteradministration of lethal doses of PO type insecticides, breathingdisappeared before the cessation of heart beats. Rats receivinglethal doses of intravenous PS type insecticides did not showhypertension, but exhibited transient cessation of breathingand heart beats. Breathing was observed after the disappearanceof heart beats. The electroencephalogram (EEG) was characterizedby spike and wave complexes. The EEG and cardiorespiratory changeswere not antagonized by atropine. It was concluded that lethalityfollowing intravenous PS type insecticides may be independentof ChE inhibition.     

PLENARY LECTURES-PL1 Toxicity of perfluorooctane sulfonate and perfluorooctanoate

Persistent perfluorinated organic compounds, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are used in a variety of industrial applications. They are very stable in the environment, distribute widely in the global environment and in wild life, and are detected in human sera.     

Case of creeping disease treated with ivermectin

We report a case of creeping disease treated successfully with ivermectin. A 46-year-old man presented with a 1-month history of pruriginous linear erythema on his right thigh after a visit to Indonesia. Although he had no history of eating raw fish or meat, he walked along the river and in the jungle without wearing shoes. Creeping disease caused by animal hookworm was strongly suspected. The presence of parasite larvae was not confirmed in biopsied skin specimens. In enzyme-linked immunosorbent assay, serum samples were negative for binding to hookworm antigens, including Ancylostoma canium , Necator americanus and Gnathostoma doloresi . He was treated with a single 12 mg oral dose (200 µg/kg) of ivermectin. The eruption and pruritus resolved within a few days after the administration and did not relapse.     

Characterization of NKT Cells in Human Peripheral Blood and Decidual Lymphocytes

PROBLEM: To examine whether natural killer (NKT) cells are present in human pregnancy decidua. METHOD OF STUDY: We calculated the percentage of CD3+CD161+Valpha 24+-NKT cells in peripheral blood and early pregnancy decidua, and analyzed intracellular cytokines, interleukin (IL)-4 and interferon (IFN)gamma in NKT cells using flow cytometry. RESULTS: A distinct subset of CD3+ CD161+ lymphocytes expressing an invariant antigen receptor encoded by the Valpha24 and Vbeta11 segment was accumulated in the decidua. In pregnant subjects the percentages of NKT cells were significantly increased in the decidua compared with peripheral blood. Both NKT cells in the decidua and the peripheral blood had an ability to rapidly produce cytokine associated with Th1 (IFNgamma) and Th2 (IL-4). Interestingly, the percentages of IL-4 and IFNgamma producing NKT cells were significantly higher in the decidua compared with the peripheral blood. CONCLUSIONS: These findings suggest that NKT cells might control the Th1/Th2 balance by producing IL-4 and IFNgamma at the feto-maternal interface.     

Antibodies to hepatitis C virus and elevated transaminase levels in a town of hyperendemicity in Iwate, Japan

In an annual survey for liver function tests in persons aged > xs35 years in Iwate Prefecture, Japan, a town was identified where high levels of alanine aminotransferase abounded. Of 5152 inhabitants aged > 35 years in this town, antibodies to hepatitis C virus (HCV) determined by enzyme-linked immunosorbent assay with HCV core peptides were detected in 798 (15.5%) people, hepatitis B surface antigen was detected in 47 (0.9%) people and antibodies to hepatitis B surface antigen and/or hepatitis B core antigen unaccompanied by surface antigenaemia were detected in 1748 (33.9%) people. Antibodies to HCV core peptides correlated closely with the antibodies detected by passive haem-agglutination with recombinant HCV proteins of the second generation. Antibodies to HCV core peptides were particularly common in one of the nine districts of the town (district 8), where 276 (45.3%) of 609 inhabitants tested positive; there were no differences in the frequency of serological markers of hepatitis B virus (HEV) infection among residents in the nine districts. Of the 798 individuals with antibodies to HCV core peptides, 257 (32.2%) were found to have elevated transaminase levels. A history of transfusion was associated with a high frequency of antibodies to HCV core peptides, except in district 8 where such antibodies were equally frequent in residents irrespective of transfusions. These results indicate an epidemiology of HCV distinct from that of HBV in this town and a very local spread of HCV, as well as a high frequency of hepatic injuries in individuals with antibodies to HCV.     

A Report on Experiments with Toyo ‘s Super-Gus-Permeable Hard Contact Lens: Paper presented at the International Contact Lens Congress,Fiji, July 1978.

Among the recent developments in the field of hard contact lenses, attention has been focused on a new type of lenses with high oxygen permeability. In 1977 the staff of the research division of the Toyo Contact Lens Co. Ltd succeeded in developing a new polymer with extremely high oxygen permeability based on an entirely new monomer made of esterifies methacrylic acid. They have named this new material ‘PHCL’, denoting a gas permeable hard contact lens. The PHCL has the following two primary features. The first feature lies in its excellent gas permeability. The permeability of the PHCL is measured to be 1.4×10^--¹⁰ml. cmlcm².sec.mmHg., which is about 2.5 times the permeability of other gas permeable hard contact lenses and about twice that of 2–Hema polymers. The second feature is the good wettability of the new material. The wettability is usually estimated by the contact angle. The contact angle of the PHCL is measured to be 23°, showing a remarkable improvement from the contact angle of PMMA which is about 63“. These two features will definitely contribute to the physiological integrity of the cornea and the comfort in wearing contact lenses. Our report includes the comparison of the PHCL with other gas permeable hard contact lenses and several soft contact lenses with respect to the following points: 1) reduction of glycogen granules in rabbits' eyes; 2) histological studies by HE staining; 3) corneal thickness changes measured by pachornetry with human eyes. The data indicates superior quality of the PHCL to other materials in terms of maintaining the normal metabolism and physiology of the cornea.