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Biomedical subjects

A Naganuma

Publications and source records attributed to A Naganuma.

At least 55 records · Page 3Linked to original sources
PubMed1993

Prevention of carcinogenicity of anticancer drugs by metallothionein induction.

We examined the efficacy of metallothionein induction in the prevention of the carcinogenic action of cis-platinum and melphalan administered repeatedly to mice over a relatively long period. The increased pulmonary metallothionein induced by bismuth or zinc compounds during the period of chemotherapy with cis-platinum or melphalan protected the mice from carcinogenesis of these drugs in the lung. These results suggested the efficacy of metallothionein inducers in suppression of carcinogenicity considered as a secondary effect of anticancer agents in cancer chemotherapy.

Animals↗
PubMed1993

Modulation of both cisplatin nephrotoxicity and drug resistance in murine bladder tumor by controlling metallothionein synthesis.

The role of metallothionein (MT) in cisplatin (cis-DDP) resistance and renal toxicity was investigated in C3H mice inoculated with mouse bladder tumor (MBT-2). C3H mice were inoculated s.c. with 1 x 10(6) MBT-2 cells/mouse on day 0. Mice were given injections of proparglyglycine (PPG) (500 mumol/kg s.c.) once a day for 3 days from day 7 to day 9 and with ZnSO4 (200 mumol/kg s.c.) once a day for 2 days from day 8 to day 9. cis-DDP (50 mumol/kg i.p.) was administered 10 days after MBT-2 cell inoculation. Since MT contents in the tumor and kidneys were significantly increased by administration of ZnSO4, both the antitumor activity of cis-DDP and its renal toxicity were reduced. However, coadministration of PPG reduced MT induction in tumor without affecting the level of renal MT. As a result, PPG could clearly overcome the MT-mediated cis-DDP resistance of tumors without compromising the protective effect exerted by renal MT on nephrotoxicity of the drug. It was suggested, therefore, that PPG may be a promising adjunct in cancer chemotherapy to overcome the drug resistance of tumors caused by the elevated level of MT.

Alkynes↗
PubMed1993

Tubular secretion and reabsorption of mercury compounds in mouse kidney.

To determine whether Hg accumulated in renal cells is secreted into the lumen of proximal tubules with intracellular glutathione (GSH) and reabsorbed by tubular cells via a gamma-glutamyltranspeptidase (gamma-GTP)-dependent process as in the case of GSH itself, the effect of postadministration of acivicin (1 mmol/kg i.p.), a gamma-GTP inhibitor, on renal Hg accumulation was investigated in mice. Renal Hg content 4 hr after injection of CH3HgCl or HgCl2 (5 mumol/kg i.v.) was decreased to 35 or 44% of control, respectively, but urinary Hg excretion was increased by acivicin administration 2 hr after injection of the mercurials. When renal GSH was decreased to 19% of control by treatment with DL-buthionine-S,R-sulfoximine (4 mmol/kg s.c.) 2 hr before acivicin injection, the increase in urinary Hg excretion caused by acivicin was suppressed. Acivicin administration 24 hr after injection of the mercurials decreased renal methylmercury content determined 2 hr after acivicin injection and increased urinary Hg excretion. The postadministration of acivicin, however, did not affect the renal content of inorganic Hg which predominantly bound to metallothionein (MT) induced by HgCl2 itself. Pretreatment with Bi(NO3)3 as a renal MT inducer diminished the effect of acivicin administered 2 hr after HgCl2 injection on renal Hg content and urinary excretion. These results suggest that methylmercury and inorganic Hg bound to ligands other than MT in renal cytosol may be secreted into the lumen of proximal tubules with intracellular GSH and be reabsorbed via a gamma-GTP-dependent process.

Absorption↗
PubMed1992

Routes for renal transport of methylmercury in mice.

To clarify the routes for renal methylmercury uptake, the effects of ureter ligation and pretreatment of probenecid, an organic anion transport inhibitor, or acivicin, a gamma-glutamyltranspeptidase (gamma-GTP) inhibitor, on renal methylmercury content were investigated in mice. For 120 min after CH3HgCl (5 mumol/kg, i.v.) injection, renal methylmercury content in bilateral ureter-ligated mice was approximately 50% lower than that of sham-operate mice. The glomerular filtration rate was reduced to about 15% of the control by ureter ligation. These results suggest an important role of glomerular filtration in the renal methylmercury uptake. Pretreatment with probenecid (0.5 or 1.0 mmol/kg, i.p.) reduced the renal methylmercury accumulation 30 min after CH3HgCl injection in a dose-dependent manner in both ureter-ligated and sham-operated mice. Urinary methylmercury excretion was not affected by probenecid pretreatment. Renal methylmercury content of ureter-ligated mice was not changed by pretreatment with acivicin (0.5 or 1.0 mmol/kg. i.p.), which was previously reported to decrease the renal methylmercury content in mice. Coadministration of GSH (10 mumol/kg, i.v.) with CH3HgCl increased the renal methylmercury uptake determined 5 min after injection in ureter-ligated mice. These results suggest that at least two transport systems play major roles in renal methylmercury uptake: one is a route from the glomeruli through the brush border membrane which is dependent on the action of gamma-GTP, and the other route is the one using an organic anion transport system through the basolateral membrane.

Animals↗
PubMed1992

Effect of coadministration of selenite on the toxicity and antitumor activity of cis-diamminedichloroplatinum (II) given repeatedly to mice.

The effect of selenite coadministration on the toxicity and antitumor activity of repeated treatment with high doses of cis-diamminedichloroplatinum (cis-DDP) was examined in mice. Sodium selenite was injected s.c. into separate abdominal sites of mice together with cis-DDP at a molar ratio of 1:3.5 (selenite to cis-DDP) on day 0. The same amount of selenite was given daily for 4 subsequent days (days 1-4). This fixed administration schedule was repeated weekly for a total of 7 weeks. Under the experimental conditions used, the lethal toxicity, renal toxicity [indicated by an increase in blood urea nitrogen (BUN) and plasma creatinine levels], hepatic toxicity (indicated by an increase in plasma GPT and GOT activity), and myelotoxicity (indicated by a decrease in the numbers of leukocytes and platelets) observed in mice given repeated doses of cis-DDP alone (15 or 25 mumol/kg, s.c.) were significantly depressed by the coadministration of sodium selenite. Treatment with cis-DDP alone (15, 20, or 25 mumol/kg, s.c.) resulted in some dose-dependent prolongation of the life span of mice transplanted either s.c. with colon adenocarcinoma 38 (colon 38) or i.p. with P388 leukemia (P388) but did not completely depress the tumor growth, and the animals died of either progressive disease or cis-DDP-induced toxicity. However, following the coadministration of 7.1 mumol/kg selenite with 25 mumol/kg cis-DDP, all of the mice transplanted either s.c. with colon 38 or i.p. with P388 survived for as long as 4 months after the end of the treatment and showed no evidence of malignancy. These results indicate that selenite coadministration enables the use of increasing doses of cis-DDP and, consequently, enhances the antitumor effect of cis-DDP by depressing its side effects.

Adenocarcinoma↗
PubMed1992

Effect of preinduction of metallothionein on paraquat toxicity in mice.

The effect of pretreatment with metallothionein (MT)-inducing metals (Zn, Cu, Bi, Co, Cd or Hg) on paraquat (PQ) toxicity was investigated in mice. PQ lethality was remarkably reduced by pretreatment with the above MT-inducing metals. The protective effect of pretreatment with these metals on PQ lethality was significantly correlated with MT levels in the lung, a target tissue of PQ toxicity, in mice administered MT-inducing metals, but not with MT in the liver or kidney. The increase in pulmonary lipid peroxidation in mice treated with PQ was significantly inhibited by Zn pretreatment. Zn was the most effective of the MT-inducing metals used in this experiment in protecting mice against PQ lethality. Of those monitored, the only pulmonary free radical scavenging factor increased by Zn pretreatment was MT. Other free radical scavenging factors (activities of superoxide dismutase, glutathione peroxidase and catalase, and concentration of non-protein thiols level) were not influenced by Zn treatment. These results indicate that the induction of pulmonary MT protects against the lethality and lung toxicity of PQ. Pulmonary MT may scavenge free radicals produced by PQ, thereby protecting against lethal pulmonary toxicity.

Animals↗
PubMed1992

Role of testosterone in gamma-glutamyltranspeptidase-dependent renal methylmercury uptake in mice.

To elucidate the mechanisms responsible for sex and age differences in renal methylmercury uptake, effects of castration and testosterone treatment on mercury content and activity of renal gamma-glutamyltranspeptidase (gamma-GTP), which supposedly plays an important role in renal mercury uptake, were investigated in mice. Between 2 and 8 weeks of age, renal methylmercury uptake in male mice determined 4 hr after injection of a nontoxic dose of methylmercuric chloride (MMC, 1 mumol/kg, sc) increased about fivefold. At 4 weeks of age, a significant sex difference in renal mercury uptake first appeared. Renal mercury content in 4-week-old male mice was twofold higher than that of females and increased with age, but remained constant in females. Small but significant (p less than 0.05) differences in mercury content in other tissues were observed, which could not account for the marked sex- and age-related differences in renal mercury concentrations. Renal gamma-GTP activity gradually increased in males with maturation, and a sexual dimorphism of renal gamma-GTP was apparent after the fourth week. Seven days after castration of 4-week-old male mice, both renal mercury content and gamma-GTP activity were decreased to the levels in females. Activity of gamma-GTP was subsequently elevated to control male levels by sc injection of testosterone (5 mg/kg/day x 7 days). In female mice, both renal mercury content and gamma-GTP activity were increased to the level of males by testosterone treatment (5 mg/kg/day x 14 days). Thus, the renal mercury content was closely correlated with changes in renal gamma-GTP activity. These results suggest that sex and age differences in renal methylmercury accumulation may be due to a difference in renal gamma-GTP activity controlled at least in part by testosterone.

Aging↗
PubMed1991

An explanation for strain and sex differences in renal uptake of methylmercury in mice.

The present investigation was designed to elucidate the mechanism for strain and sex differences in renal methylmercury accumulation, in five mouse strains, viz. BALB/cA, C57BL/6N, CBA/JN, C3H/HeN and ICR. Strain and sex comparisons of factors which influence renal mercury accumulation were made. Strain and sex differences were observed in renal mercury accumulation 4 h after methylmercuric chloride (MMC) (1 mumol/kg, s.c.) injection. Glutathione (GSH) content in liver and kidney showed significant strain and sex differences. Pretreatment with 1,2-dichloro-4-nitrobenzene (DCNB), to deplete hepatic GSH without affecting renal non-protein thiol (NPSH) level, led to a dose-dependent decrease in hepatic and plasma GSH concentrations that correlated with decreased mercury levels in the kidney 10 min after MMC (1 mumol/kg, i.v.) injection. This indicates that hepatic and plasma GSH levels are related to mercury accumulation into the kidney. Renal gamma-glutamyltranspeptidase (gamma-GTP) activity significantly varied among the strains, and in BALB/cA and ICR, renal gamma-GTP activity in males was about 2-fold higher than that in females. Renal gamma-GTP activity was also correlated with the renal mercury content. These results suggest that strain and sex differences in renal accumulation of mercury are attributable to differences in tissue GSH content and possibly to differences in renal gamma-GTP activity.

Animals↗
PubMed1991

Effect of the administration of bismuth nitrate on radiogenic thymoma induction in mice.

Metallothionein functions as a radical scavenger protecting cells from the indirect effect of radiations. We investigated the effect of bismuth nitrate, an efficient inducer of metallothionein, on acute and late effects of radiation in mice. Metallothionein contents were examined in several organs after the administration of bismuth nitrate. The content in bone marrow increased 2-fold in the treated as compared to the control mice. This treatment protected irradiated mice from bone marrow death and increased the number of endogenous spleen colonies. The metallothionein content in the ileum did not change after treatment with bismuth nitrate. Mice were not protected by bismuth nitrate when exposed to 9 Gy of X-rays. This suggests that this agent does not protect from gastrointestinal death. The incidence of X-ray-induced thymic lymphomas was lowered by the administration of bismuth nitrate in mice exposed to four fractionated doses of 1.3 Gy of X-rays. These results indicate that bismuth nitrate effectively modified both acute and late effects of X-rays by inducing metallothionein in the target tissues.

Animals↗
PubMed1990

Cellular glutathione as a determinant of sensitivity to mercuric chloride toxicity. Prevention of toxicity by giving glutathione monoester.

Depletion of glutathione (GSH) by treatment of mice with buthionine sulfoximine (BSO), an effective inhibitor of gamma-glutamylcysteine synthetase, markedly enhanced (about 10-fold) the lethal and renal toxicity of mercuric chloride. The lethal toxicity of HgCl2 was prevented by administration of GSH monoester; this was observed in mice pretreated with BSO and given a low dose of HgCl2, and also in untreated mice that were given a much higher dose of HgCl2. In contrast, administration of GSH did not protect. Since administered GSH is not transported effectively into cells, whereas GSH monoester is transported and split intracellularly to GSH, the findings indicate that protection against HgCl2 requires intracellular GSH. The experimental approaches used here suggest that cellular GSH is a major determinant of sensitivity to HgCl2 toxicity, and also that administration of GSH esters may be useful for prevention of HgCl2 toxicity.

Animals↗
PubMed1990

Role of gamma-glutamyltranspeptidase in renal uptake and toxicity of inorganic mercury in mice.

The role of renal glutathione (GSH) metabolism as a mediating factor in the renal uptake and toxicity of inorganic mercury was investigated in mice by preadministering a gamma-glutamyltranspeptidase (GGT) inhibitor, acivicin. Pretreatment with acivicin (0.25, 1.0 or 2.5 mmol/kg, i.p.) led to a dose-dependent decrease in renal mercury content and increases in mercury and GSH contents in urine measured 2 h after HgCl2 injection (18 mumol/kg, i.v.). Acivicin pretreatment also ameliorated the renal and lethal toxicity caused by administration of inorganic mercury. Treatment of the mice with 1,2-dichloro-4-nitrobenzene (DCNB, 2.5 mmol/kg, i.p.), a specific depletor of hepatic GSH, prior to HgCl2 injection substantially reduced renal Hg content and consequently reduced the renal damage. In addition, coadministration of GSH (36 mumol/kg, i.v.) with HgCl2 increased the renal Hg content measured 5 min after HgCl2 injection to 2.6 fold higher than that of mice treated with HgCl2 alone. These results suggest that renal uptake of inorganic mercury, which is supposedly transported to the kidney as a mercury-GSH complex, is dependent on a reaction catalyzed by GGT on the outer surface of the renal brush border membrane in the same manner as the metabolism of GSH.

Animals↗
PubMed1990

Absorption of methylmercury compounds from rat intestine.

Intestinal absorption of methylmercury complexed with non-protein sulfhydryl compounds (NPSHs) as occurs in bile was studied by means of direct injection of mercury compounds into ligated intestinal segments of rats. The extent of absorption of methylmercury-cysteinylglycine (MM-CysGly) was similar to that of methylmercury-cysteine (MM-Cys) and 1.5 times larger than that of methylmercury-glutathione (MM-GSH). This results suggested that MM-CysGly, which is recognized as a major component of methylmercury in rat bile, can be easily reabsorbed from the intestine. These results indicate that not only MM-GSH and MM-Cys but also MM-CysGly may play important roles in the intestinal reabsorption of methylmercury during its enterohepatic circulation. When the ligated intestine was pretreated with probenecid and acivicin, the intestinal absorption of MM-GSH was depressed much more than in the case of treatment with acivicin alone. This indicates the possibility that there are at least two systems for intestinal transport of MM-GSH, i.e. gamma-glutamyltranspeptidase (GGT)-dependent and -independent systems.

Animals↗
PubMed1990

Protection against cisplatin toxicity by administration of glutathione ester.

The role of cellular glutathione in the prevention of toxicity due to the anti-cancer drug cisplatin (cis-diamminedichloroplatinum) was explored in mice treated with buthionine sulfoximine (BSO), a selective inhibitor of gamma-glutamylcysteine synthetase (and therefore of glutathione synthesis), and with glutathione and glutathione monoisopropyl ester. Pretreatment of mice with BSO enhanced the lethal toxicity of cisplatin by about twofold. Administration of glutathione ester (dose, 2.5-7.5 mmol/kg) protected against lethal cisplatin toxicity; glutathione was also effective, but much less so. Glutathione ester, in contrast to glutathione, is effectively transported into cells and split to glutathione intracellularly. The previous findings that administered glutathione does not protect against lethal toxicity due to cadmium ions and mercuric ions, whereas glutathione ester does, suggest that intracellular glutathione is required for protection against these heavy metal ions. That administration of glutathione has a protective effect on cisplatin toxicity suggests that the toxic effects of cisplatin may be exerted both intracellularly and extracellularly, and that extracellular glutathione (or its degradation products) may form a complex with cisplatin extracellularly. The finding that glutathione ester is more effective than glutathione in protecting against the toxicity of cisplatin suggests that use of glutathione ester may be therapeutically advantageous.

Animals↗
PubMed1989

Prevention of adverse effects of gamma-ray irradiation after metallothionein induction by bismuth subnitrate in mice.

The effect of preinduction of metallonthionein (MT) by bismuth subnitrate (BSN) on the adverse effects and antitumor activity of gamma-ray irradiation was investigated in mice. Preinduction of MT by oral administration of BSN significantly reduced the lethal effects and bone marrow injury caused by total body irradiation with gamma-rays. A significant increase in the MT concentration in bone marrow was observed in mice treated with BSN. In tumor-bearing mice, pretreatment with BSN did not compromise the antitumor activity of gamma-ray irradiation although bone marrow injury was remarkably suppressed. These results suggest that BSN pretreatment is an effective method for protection against side-effects in radiotherapy.

Adenocarcinoma↗
PubMed1989

Optimum schedule of selenium administration to reduce lethal and renal toxicities of cis-diamminedichloroplatinum in mice.

The optimum conditions of selenium administration to reduce the side effects of a single dose of cis-diamminedichloroplatinum (cis-DDP) in mice were examined. The best effects against lethal toxicity of cis-DDP was obtained when sodium selenite was administered subcutaneously (s.c.) to mice simultaneously with s.c. injected cis-DDP at a molar ratio of 1 to 3.5 (sodium selenite to cis-DDP) on the first day and the same amount of selenite was given daily for four subsequent days. This coadministration of selenite completely depressed not only lethal toxicity of cis-DDP but also its renal toxicity (indicated by increased blood urea nitrogen values) and intestinal toxicity (indicated by the incidence of diarrhea) which were usually observed in the mice treated with cis-DDP alone. Furthermore, coadministration of selenite did not compromise the antitumor activity of cis-DDP against several transplantable tumors in mice. Therefore, the administration schedule of selenite with cis-DDP described above may be useful for cancer chemotherapy.

Animals↗
PubMed1989

[Metallothionein as a resistance factor for antitumor drugs].

Metallothionein (MT), a metal binding protein induced by bismuth and other heavy metals, has been proved to have a potential to prevent toxic side effects of several antitumor drugs. It has also been demonstrated that the induction of MT in tumor tissues diminishes the antitumor activity of the drugs as well. These facts suggest a possibility that MT may play an important role in acquiring multi-drug-resistance in tumor cells. Thus, we were encouraged to examine the sensitivity of cultured cells overexpressing MT to various antitumor drugs which differ from each other in the mechanism of action. Cadmium-resistant cells (HeLa-R) were obtained from HeLa S3 cells (HeLa-S) by successive cultivation in a medium containing 100 microM CdCl2. MT level in HeLa-R was 180 times higher than that of HeLa-S. Comparison of the sensitivity of these two strains to the antitumor drugs, such as, cis-diamminedichloroplatinum (cis-DDP), adriamycin (ADR), peplomycin (PEP) and melphalan (MEL), revealed that HeLa-R was significantly more resistant to these drugs than HeLa-S. Further, there was no significant discrepancy between these strains, either in the level of major radical scavenging factors other than MT or in the cellular uptake of the drugs. The experimental results described above appear to support the hypothesis that MT may act as a multi-drug-resistance factor in tumor tissues.

Animals↗
PubMed1988

Involvement of cardiac metallothionein in prevention of adriamycin induced lipid peroxidation in the heart.

The effect of pretreatment of mice with heavy metals: Zn, Cu, Bi, Co, Cd or Hg, against lethal and cardiac toxicity of adriamycin (ADR) was investigated. The lethal toxicity of ADR was significantly reduced by pre-administration of these metals except for Cu. The levels of both malondialdehyde and conjugated dienes, determined as indicators of lipid peroxidation in the heart, markedly increased with ADR administration, but the increases were significantly prevented by the pre-administration of Zn, Bi or Cd. The survival rate of mice after ADR injection was significantly correlated with metallothionein (MT) levels in the hearts which was increased by the injection of each metal, but was not correlated with those in the liver and kidneys. A significant negative correlation between the cardiac MT concentrations and the levels of lipid peroxidation in the hearts was also observed. These results suggest that increased MT synthesis in the heart may be involved in the protective effect of the heavy metals tested against the lethal and cardiac toxicities of ADR.

Animals↗