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Biomedical subjects

N Koga

Publications and source records attributed to N Koga.

At least 127 records · Page 7Linked to original sources
PubMed1986

S-[2-(N7-guanyl)ethyl]glutathione, the major DNA adduct formed from 1,2-dibromoethane.

The reaction of 1,2-dibromoethane and glutathione with DNA in the presence of glutathione S-transferase results in the formation of a single major DNA adduct, which can be released by thermal hydrolysis at neutral pH and separated by octadecylsilyl and propylamino high-performance liquid chromatography. The same DNA adduct is the only major one formed in livers of rats treated with 1,2-dibromo[1,2-14C]ethane. The DNA adduct was identified as S-[2-(N7-guanyl)ethyl]glutathione: (1) The chromatographic behavior was altered by treatment with gamma-glutamyl transpeptidase or Streptomyces griseus protease. (2) The molecular ions observed in positive and negative mode fast atom bombardment mass spectrometry were those expected for the structure when either glycerol or a mixture of dithiothreitol and dithioerythritol was used as the bombardment matrix. (3) The two-dimensional 1H NMR correlated spectroscopy spectrum of the DNA adduct was compared to the spectra of glutathione, oxidized glutathione, and N7-methylguanine and found to be consistent with the assigned structure. No evidence for in vitro or in vivo opening of the guanyl imidazole ring was observed under these conditions. The structure of the adduct supports a pathway involving enzyme-catalyzed conjugation of 1,2-dibromoethane with glutathione, non-enzymatic dehydrohalogenation of the resulting half-mustard to form a cyclic episulfonium ion, and attack of the N7 nitrogen of DNA guanine on the episulfonium ion to generate this major DNA adduct, which may be related to the carcinogenicity of this chemical.

Animals↗
PubMed1986

A growth-promoting factor existing on the body surface of rats.

Effects of water-soluble matter adhering to rat hairs on fibroblasts were examined. The dialysate of the wash water of rat hairs significantly enhanced the cell proliferation of both diploid human dermal fibroblasts (DHDF) and diploid rat fibroblasts (DRDF). The cell growth-promoting activity was partially purified by a gel filtration column chromatography. The activity permeates through a ultrafiltration membrane (M.W. cut off: 500). Analyses of its chemical nature show that it is soluble in water, dimethyl sulfoxide or acetonitrile, insoluble in other organic solvents examined, stable to heat or pH shock, and resistant to a bacterial protease.

Acetonitriles↗
PubMed1986

Covalent binding of 1,2-dihaloalkanes to DNA and stability of the major DNA adduct, S-[2-(N7-guanyl)ethyl]glutathione.

The major DNA adduct formed from the carcinogen ethylene dibromide (1,2-dibromoethane, EDB) is S-[2-(N7-guanyl)ethyl]glutathione, resulting from the reaction of guanyl residues with the half-mustard S-(2-bromoethyl)glutathione, which is generated by glutathione S-transferase-catalyzed conjugation of EDB with glutathione. The half-life of the alkylating species [putative S-(2-bromoethyl)glutathione or the derived episulfonium ion] was estimated to be less than 10 s. However, the stability was enough for approximately half of the alkylating metabolites to leave isolated rat hepatocytes before reacting with nucleic acids. Treatment of isolated rat hepatocytes with diethylmaleate decreased covalent binding of EDB to DNA, but treatment with 1-phenylimidazole did not, consistent with the view that conjugative metabolism is of greater importance than oxidation with regard to DNA binding. When EDB was administered to rats in vivo, only one major adduct, S-[2-(N7-guanyl)ethyl]glutathione, was formed in liver or kidney. S-[2-(N7-Guanyl)ethyl]glutathione was found in liver and kidney DNA of rats treated with 1,2-dichloroethane, but other adducts were also present. The gamma-glutamyl transpeptidase inhibitor AT-125 [L-(alpha-(5S)-alpha-amino-S-chloro-4,5-dihydro-5-isoxazoleacetic acid] did not affect the level of EDB bound to DNA by glutathione-fortified rat kidney homogenates or bound to liver or kidney DNA in vivo. The in vitro half-life of S-[2-(N7-guanyl)ethyl]glutathione in calf thymus DNA was 150 h; the half-life of the adduct in rat liver, kidney, stomach, and lung was between 70 and 100 h. Isolated S-[2-(N7-guanyl)ethyl]glutathione did not react with DNA to form new adducts. These results provide a further basis for understanding the carcinogenic action of 1,2-dihaloethanes.

Animals↗
PubMed1985

The tissue distribution of diazinon and the inhibition of blood cholinesterase activities in rats and mice receiving a single intraperitoneal dose of diazinon.

The tissue distribution of diazinon and the inhibition of cholinesterase (ChE) activities in plasma, erythrocyte and brain were investigated using male rats and mice which received a single intraperitoneal (i.p.) dose of diazinon (20 or 100 mg/kg body wt) in olive oil. The blood diazinon level was estimated to reach a maximum at 1-2 h after the i.p. administration. It was demonstrated that the diazinon residue levels are the highest in the kidney, when comparing the distribution of diazinon among liver, kidney and brain in the animals after dosing. It was indicated that the ChE inhibition by diazinon exposure is greater in the plasma than in the erythrocytes for male mice, while its inhibition is greater in the erythrocytes for male rats. Brain ChE activity was also inhibited markedly in the mice after dosing.

Animals↗
PubMed1985

Effect of liver S9 from 3,4,5,3',4'-pentachlorobiphenyl-pretreated rats on the mutagenic activity of the various carcinogens toward Salmonella typhimurium TA 98.

Effects of liver 9000 X g supernatant fraction from 3,4,5,3',4'-pentachlorobiphenyl- and 2,4,5,2',4',5'-hexachlorobiphenyl-pretreated rats (PenCB-S9 and HexCB-S9, respectively) on the mutagenic activities of well-known carcinogens, benzo-[a]pyrene (BP), Glu-P-1 (2-amino-6-methyldipyrido [1,2-a:3',2'-d]imidazole), Trp-P-1 (3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole), and aflatoxin B1 (AFB), toward Salmonella typhimurium TA 98 have been described. Although the mutagenic activities of all of these carcinogens were enhanced by these S9, PenCB-S9 especially highly activated BP, Glu-P-1, and Trp-P-1. The ability of PenCB-S9 to activate the carcinogens was much higher than that of liver 9000 X g supernatant fraction from 3-methylcholanthrene-pretreated rats (MC-S9). PenCB-S9 enhanced the mutagenic activity of BP 8 times higher than MC-S9, while Glu-P-1 and Trp-P-1 were activated by PenCB-S9 twice as much as by MC-S9. Effect of HexCB-S9 on the mutagenic activities of the above-mentioned three carcinogens was much less than those of PenCB- and MC-S9 and a little higher than that of 9000 X g supernatant fraction from rats pretreated with phenobarbital. As for AFB, phenobarbital was the most potent inducer, and HexCB and PenCB were next to this. Data suggest that PenCB is a strong inducer of P-448 species which activate environmental toxicants.

Aflatoxin B1↗
PubMed1985

Accumulation, excretion and effects on hepatic enzymes of polychlorinated quaterphenyl congeners in rats.

Six skeletal congeners of polychlorinated quaterphenyls (PCQs), namely polychlorinated o-quaterphenyl (2,2'-PCQ), 2,3'-diphenylbiphenyl (2,3'-PCQ), 2,4'-diphenylbiphenyl (2,4'-PCQ), m-quaterphenyl (3,3'-PCQ), 3,4'-diphenylbiphenyl (3,4'-PCQ) and p-quaterphenyl (4,4'-PCQ), were orally administered to Wistar rats at a dose of 10 mg/rat. On the 5th day after administration of PCQs, the rats were examined for accumulation of PCQ congeners, hepatic enzyme activities and organ weight changes. Accumulation of 3,3'-PCQ, 3,4'-PCQ and 4,4'-PCQ were 1.5-3.2% of dose in the liver, while those of 2,2'-PCQ, 2,3'-PCQ and 2,4'-PCQ were only 0.1 to 0.2%. The amount of 4,4'-PCQ accumulated in the mesenteric adipose tissue, 20 micrograms/rat, was much higher than those of other PCQ congeners. Large amounts of the PCQ congeners administered were excreted in the feces on the first day, accounting for 96 to 98% of dose for 2,2'-PCQ and 4,4'-PCQ, and 55 to 75% for the other PCQ congeners, and the daily excretions of PCQs after the second day were very small, less than 10% of the dose. Benzo [a] pyrene 3-hydroxylase activity was significantly depressed by the treatment with 3,3'-PCQ, 3,4'-PCQ and 4,4'-PCQ, contrasting to the toxic congeners of polychlorinated biphenyls and dibenzofurans which enhanced markedly this enzyme activity. DT-Diaphorase activity was also depressed by the treatment with 2,3'-PCQ, 2,4'-PCQ and 3,4'-PCQ. Significant atrophy of the thymus was observed by the treatment with 4,4'-PCQ.

Adipose Tissue↗
PubMed1985

Inductive effect on hepatic enzymes and toxicity of congeners of PCBs and PCDFs.

The present paper describes a marked induction of liver microsomal cytochrome P-450 and cytosolic DT-diaphorase to cause possible disorder of steroid homeostasis and promotion of carcinogenicity of 4-nitroquinoline N-oxide (4-NQO) in rats by pretreatment with 3,4,5,3',4'-pentachlorobiphenyl (PenCB) or 2,3,4,7,8-pentachlorodibenzofuran (PenCDF). The animals were sacrificed 5 days after the pretreatment. These induction experiments showed that 7 alpha-hydroxylation of both progesterone and testosterone in liver microsomes was selectively increased to a great extent, but hydroxylations at the 2 alpha-, 6 beta- and 16 alpha-positions were depressed, together with 5 alpha-reduction. From the same microsomes, three of the strongly induced P-450 isozymes, i.e., high- and low-spin P-448s and P-452, were purified. The last isozyme was most responsible for 7 alpha-hydroxylation of testosterone. The pretreatment, also increased activity of DT-diaphorase and reduction of 4-NQO about 10-fold in liver 9000g supernatants. This reduction of 4-NQO was solely catalyzed by DT-diaphorase and the only product was 4-hydroxylaminoquinoline N-oxide, a proximate carcinogen, indicating that the pretreatment strongly increased production of a proximate carcinogen from 4-NQO. Such an enhancement of the metabolic activation of 4-NQO by the pretreatment was also observed to some extent in the lung and the skin. Persistency of PenCB and PenCDF in the liver of rats was also discussed.

4-Nitroquinoline-1-oxide↗