Yoshiki Sugihara

Comparison between in vivo mutagenicity and carcinogenicity in multiple organs by benzo[a]pyrene in the lacZ transgenic mouse (Muta Mouse).

To evaluate whether the in vivo mutagenicity test system using the lacZ transgenic mice (Muta Mouse) may be applied to carcinogenesis studies, both the in vivo mutagenicity and carcinogenicity of benzo[a]pyrene (BP) was tested in mice under the same administration conditions. The eleven organs of the mice on the 14th day after the final oral administration of BP at a dose of 125 mg kg(-1) day(-1) or corn oil for 5 consecutive days were tested for in vivo mutation by the positive-selection method. The data show that the colon had the highest lacZ mutant frequency (37-fold increase over the spontaneous frequency), followed by the ileum > forestomach > bone marrow, spleen > glandular stomach > liver, lung > kidney and heart. No significant mutations were found in the brain. These results may suggest that, in general, the organs with rapidly proliferative tissues have a marked increase in vivo mutant frequencies under the conditions of this experimental design. The forestomach and lymphatic organs including the spleen (malignant lymphoma) were the main target organs for BP carcinogenesis by 5 daily oral doses of 75 and 125 mg kg(-1) day(-1). These results suggest that the mutation results from the transgenic assay with BP reflect the carcinogenicity of BP in the mouse. They also indicate, however, that the magnitude of the in vivo lacZ mutant frequencies induced by BP in different organs did not fully correlate with the target organs for carcinogenicity.

Mutagenicity of dihydroxybenzenes and dihydroxynaphthalenes for Ames Salmonella tester strains.

The mutagenicity of 3 dihydroxybenzene (DHB) and 9 dihydroxynaphthalene (DHN) isomers was examined by using 5 different Ames Salmonella mutagenicity tester strains in the presence and absence of phenobarbital and 5,6-benzoflavone-treated rat liver S9-mix. Of the 3 DHB isomers, 1,4-DHB (hydroquinone) was mutagenic, and of the 9 DHN isomers, 1,3-DHN (naphthoresorcinol), 1,4-DHN (hydronaphthoquinone), 1,6-DHN and 1,7-DHN were mutagenic. Mutagenicity of all the compounds tested was observed in the absence of S9-mix, while 1,4-DHN and 1,6-DHN were also mutagenic in the presence of S9-mix. The mutagenicity of 1,4-DHB and 1,4-DHN for TA104, which is a strain sensitive to oxidative mutagens, was almost completely or partially inhibited by superoxide dismutase (SOD) and/or catalase, indicating the involvement of activated oxygen species in mutagenesis. Furthermore, from the finding that the 4 DHNs were mutagenic for TA2637, the strain sensitive to frameshift mutagens, it is possible that the mutagenicity of DHNs for S. typhimurium was also attributable to DNA adducts that form with quinones and/or semiquinones through oxidation of DHNs. The mutagenicity of 1,3-DHN, which showed the largest number of revertants in strains TA100, TA98, TA2637 and TA104, was greatly decreased, when their pKM101 plasmid-deficient strains, TA1535, TA1538, TA1537 and TA2659 were used. This observation suggests that an SOS repair system was involved in the mutagenesis of 1,3-DHN for S. typhimurium.

Enhancing Effects of Fluorescein on β‐Lactam Rash II: Enhancing Effects of Fluorescein on Generalized Rash Induced by β‐Lactam Antibiotics in Guinea Pigs

Healthy volunteers, who were receiving intravenous injections of cefclidin (CFCL) with frequent concomitant use of fluorescein (F) and oxybuprocain (O) in the eyes for measurement of ocular tension, developed drug eruptions at the high frequency of 66.7%. The injection of CFCL alone induced the eruptions at an incidence of 2.8%. The cause of this high eruption rate was thought to be the simultaneous treatment with F and/or O. Therefore, we conducted experiments with CFCL‐induced generalized rash (GR) in guinea pigs. Guinea pigs treated with F and O during both the phases of immunization and intraperitoneal elicitation developed CFCL rashes at a high frequency. This CFCL‐rash was augmented by the treatment with F during either phase, but not by the treatment with O. Skin testing induced delayed type hypersensitivity (DTH) reaction to O in some animals, but the DTH to F was not induced in animals immunized with F in complete Freunds adjuvant. Furthermore, F augmented rashes induced not only by CFCL but also by other β‐lactam antibiotics such as cefsulodin and sulbenicillin.