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Biomedical subjects

A Nishikawa

Publications and source records attributed to A Nishikawa.

At least 145 records · Page 8Linked to original sources
PubMed1996

Prevention by 2-mercaptoethane sulfonate and N-acetylcysteine of renal oxidative damage in rats treated with ferric nitrilotriacetate.

Ferric nitrilotriacetate (Fe-NTA) is a renal toxicant and carcinogen in rats and mice. We found that its administration results in formation of 4-hydroxy-2-nonenal (HNE) in the renal proximal tubule cells of rats, and 8-hydroxydeoxyguanosine (8-OHdG) adducts in their DNA, suggesting a role for oxidative stress. Since 2-mercaptoethane sulfonate (MESNA) and N-acetylcysteine (NAC), administered orally, have been shown to increase the kidney levels of free thiol groups, their influence on the renal toxicity and carcinogenicity induced by Fe-NTA was examined in the present study. Male Wistar rats were intraperitoneally injected with Fe-NTA (12 mg Fe/kg), and MESNA (100 mg/kg) or NAC (200 mg/kg) was given orally 1 h before and 1 h after this treatment. The animals were killed for tissue analyses 3 h after the Fe-NTA exposure. In accord with our previous reports, HNE-modified protein was detected in the proximal tubules of Fe-NTA-treated rats by means of immunohistochemistry. Likewise, levels of 8-OHdG in the renal nuclear DNA, lipid peroxides as thiobarbituric acid-reactive substances in the kidneys, and blood urea nitrogen and creatinine in the serum were significantly increased by the Fe-NTA treatment. All of these changes were completely inhibited by oral administration of MESNA or NAC. These results suggest that both of these compounds can prevent the oxidative stress induced by Fe-NTA.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1996

Chemopreventive effects of 3-phenylpropyl isothiocyanate on hamster lung tumorigenesis initiated with N-nitrosobis(2-oxopropyl)amine.

The chemopreventive effects of 3-phenylpropyl isothiocyanate (PPITC) were investigated in N-nitrosobis(2-oxopropyl)amine (BOP)-initiated hamsters. A total of 120 female 5-week-old hamsters were divided into 6 groups. Animals in groups 1-3, each consisting of 30 hamsters, were twice sc injected 7 days apart as an initiation treatment. Hamsters in groups 1 and 2 were respectively given 100 microM and 10 microM of PPITC by gavage 2 h prior to each BOP treatment. Animals in group 3 were treated with BOP alone, serving as an initiation-positive control. Animals in groups 4-6, each consisting of 10 hamsters, were given 100 microM or 10microM of PPITC alone, or non-treated, thus being available as matched negative controls to groups 1-3. At termination (experimental week 51 after the first BOP injection), the incidences of lung adenomas and/or adenocarcinomas were significantly decreased in groups 1 and 2 as compared to the group 3 value (p<0.01). The combined lung tumor incidences were inhibited by 94% and 59% at 100 and 10 microM doses, respectively. The inhibitory effects of PPITC were thus dose-dependent. The data for multiplicity of lung tumors dramatically illustrated the inhibitory effects of PPITC, and there were also statistically significant differences in the chemopreventive effect between 100 microM and 10 microM PPITC treatments. On the other hand, the PPITC treatments did not significantly modulate the development of neoplastic lesions in the pancreas,liver and kidney, although the treatments did show inhibitory tendencies, except on the liver lesions. Under present experimental conditions, PPITC itself did not exhibit tumorigenicity or apparent toxicity. The results in the present study thus clearly indicate that PPITC has an effective chemopreventive action on BOP-induced lung tumorigenesis in hamsters.

Animals↗
PubMed1996

Production of agglutinating monoclonal antibody against antigen 8 specific for Cryptococcus neoformans serotype D.

A hybridoma (clone CRND-8) that produced agglutinating monoclonal antibody (MAb) against Cryptococcus neoformans serotype D was established by using a soluble capsular polysaccharide-keyhole limpet hemocyanin conjugate for immunization. The isotype was immunoglobulin M(kappa). Specificity was determined by cell slide agglutination and enzyme-linked immunosorbent assay (ELISA). In both tests, the MAb reacted to serotypes D and A-D but not to serotypes A, B, and C. Furthermore, the specificity of the MAb determined by ELISA was the same as that of polyclonal antibody factor serum (PAb factor) 8, which showed high-level reactivity with serotypes D and A-D. These results supported the deduced specificity of the PAb-based antigenic factor 8. A total of 15 isolates of serotypes D and A-D but no serotype A isolates reacted with the MAb in cell slide agglutination tests. CRND-8 MAb can be used in place of PAb factor 8 for serotyping C. neoformans isolates and for the analysis of the antigen 8 epitope.

Agglutination Tests↗
PubMed1996

Apoptosis in adult mouse testis induced by experimental cryptorchidism.

Induction of cryptorchidism in the mouse causes infertility due to disruption of spermatogenesis including reduction of germ cells; however, the cellular mechanism responsible for the degenerative changes in cryptorchid testis is still unclear. In surgically induced bilateral cryptorchidism of 3-month-old C57BL/Tw mice, cellular changes in the cryptorchid testis were studied 1, 2, 3, 7, 14 and 21 days after the operation by electron microscopy, DNA fragmentation, in situ 3'-end labeling, serum and testicular testosterone measurements and gene expression. Although the testis showed DNA fragmentation even in intact mice, the cryptorchidism increased the degree of the fragmentation at 1 postcryptorchidism (p.c.) day. Apoptosis was encountered mainly in spermatids and spermatocytes. The number of apoptotic cells in the cryptorchid testis showed a 7-fold increase at 1 p.c day as compared to the intact testis, then it gradually decreased. Serum testosterone levels showed a significant decrease at 2 p.c. days and remained low thereafter. Expression of transforming growth factor-beta 2 (TGF-beta 2), TGF-beta 3, tumor necrosis factor-alpha receptor and Fas mRNAs increased in the cryptorchid testis within 24 h after the operation. In lpr(cg) and lpr mice lacking functional Fas, gld mice lacking functional Fas ligand and lpr(cg)-gld mice lacking both functional Fas and Fas ligand, the experimental cryptorchidism also induced apoptosis in germ cells at 1 p.c. day. The present results indicate that cryptorchidism induces apoptotic dell death in germ cells, and that testosterone reduction and the Fas system may not be significantly involved in the apoptosis of male germ cells.

Animals↗
PubMed1996

[A 13-week subchronic toxicity study of gardenia blue in F344 rats].

A 13-week oral toxicity study of gardenia blue was performed in male and female F344 rats at the dose levels of 5.0, 2.5, 1.25, 0.6 and 0% in the diet, to determine the maximum tolerable dose (MTD) for subsequent investigation of carcinogenicity. Rats were randomly allocated to 5 groups, each consisting of 10 males and 10 females. No groups showed decreases in body weight gain and food intake, and all animals survived until the end of the experiment. A dose-dependent decrease in number of platelets was observed in females treated with gardenia blue in hematological examination, but not in males. No histopathological change, relating to the treatment, in megakaryocyte which is the progenitor cell of platelets was observed in the treated-females. Serum biochemistry revealed increases in GOT and GPT in both sexes treated with the 5.0% and 2.5% gardenia blue, as compared to the control value. However, these were not considered to be specific changes because of lack of any clear dose response. In addition, no histopathological changes indicating obvious toxicity of gardenia blue were observed in the liver of both sexes treated with gardenia blue. Based on these data, the MTD of gardenia blue for both sexes in F344 rats was considered to be 5.0% or more in the diet.

Alanine Transaminase↗
PubMed1995

Enhancement of GST-P positive liver cell foci development by a medium-term carcinogenicity bioassay using repeated administration of D-galactosamine.

This study was performed for developing a new medium-term carcinogenicity bioassay treated with D-galactosamine (DGA) as a non-surgical method without partial hepatectomy (PH). In male F344 rats initiated with diethylnitrosamine (DEN, 200 mg/kg i.p.), enhancing effects of DGA (300 mg/kg i.p.) given twice 3 weeks apart during the promotion procedure with 2-acetylaminofluorene (2-AAF, 0.01% in diet) were compared along with those of PH by analyzing preneoplastic glutathione S-transferase placental form positive (GST-P+) hepatocyte foci as endpoint marker lesions. The DGA treatment did not affect the body weight gain whereas the PH treatment caused a transient body weight loss. Although both bioassay protocols were effective to detect the potential hepatocarcinogenicity of 2-AAF, the number and area of GST-P positive foci per cm2 were larger in the bioassay using DGA than in that using PH, the number being statistically significant (P < 0.05). Our results thus suggest that the present bioassay protocol with repeated administration of DGA instead of PH may offer a new and sensitive method to screen large numbers of environmental carcinogens.

2-Acetylaminofluorene↗
PubMed1995

Dose-dependent promotion effects of potassium chloride on glandular stomach carcinogenesis in rats after initiation with N-methyl-N'-nitro-N-nitrosoguanidine and the synergistic influence with sodium chloride.

The modifying effects of potassium chloride (KCl) ingestion on glandular stomach carcinogenesis were investigated in male Wistar rats induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and were compared with those of sodium chloride (NaCl). A total of 120 male 6-week-old Wistar rats were divided into six groups, each consisting of 20 animals. After initiation of treatment with a MNNG solution (100 parts/million) as their drinking water for 10 weeks, rats were fed a diet supplemented with 5% NaCl, 2.5% NaCl, 2.5% NaCl plus 2.5% KCl, 5% KCl, 2.5% KCl, or a basal diet alone for the following 62 weeks. Under this experimental condition, there were no statistical differences in the final body weights between groups. The incidences of adenocarcinomas in the glandular stomachs were significantly higher in the 5% NaCl and combined 2.5% NaCl-plus-2.5% KCl groups (P < 0.05 and 0.01) than in the MNNG alone (control) group. The incidences of atypical or precancerous hyperplasias in the glandular stomachs were increased significantly by the 5% NaCl, 2.5% NaCl-plus-2.5% KCl, and 5% KCl treatments (P < 0.05 or 0.01). The multiplicities of adenocarcinomas were significantly greater in the 5% NaCl, 2.5% NaCl, and combined NaCl-plus-KCl groups (P < 0.05 or 0.01) compared with the control value. The multiplicity data for atypical hyperplasias were most striking; namely, their multiplicities were increased significantly by the treatments of NaCl or KCl (P , 0.01) in a clear dose-dependent manner and enhanced synergistically by the combined treatment of NaCl and KCl. Because the concentrations of KCl used in this study were about 1.3 times lower than those of NaCl on a molar basis, although the doses of each chemical were exactly the same on a weight-percent basis, it is suggested that the enhancing effects of KCl might not be much different from those of NaCl. The results in the present study thus indicate that, similarly to NaCl, KCl ingestion exerts dose-dependent promoting effects and a synergistic influence with NaCl when given during the postinitiation phase of two-stage glandular stomach carcinogenesis in rats.

Animals↗
PubMed1995

Transcriptional repression by human adenovirus E1A N terminus/conserved domain 1 polypeptides in vivo and in vitro in the absence of protein synthesis.

The human adenovirus E1A 243R protein (243 residues) transcriptionally represses a set of cellular genes that regulate cellular growth and differentiation. We describe two lines of evidence that E1A repression does not require cellular protein synthesis but instead involves direct interaction with a cellular protein(s). First, E1A 243R protein represses an E1A-repressible promoter in the presence of inhibitors of protein synthesis, as shown by cell microinjection-in situ hybridization. Second, E1A 243R protein strongly represses transcription in vitro from promoters of the E1A-repressible genes, human collagenase, and rat insulin type II. Repression in vitro is promoter-specific, and an E1A polypeptide containing only the N-terminal 80 residues is sufficient for strong repression both in vivo and in vitro. By use of a series of E1A 1-80 deletion proteins, the E1A repression function was found to require two E1A sequence elements, one within the nonconserved E1A N terminus, and the second within a portion of conserved region 1 (40-80). These domains have been reported to possess binding sites for several cellular transcription regulators, including p300, Dr1, YY1, and the TBP subunit of TFIID. The in vitro transcription-repression system described here provides a powerful tool for the further analysis of molecular mechanism and the possible role of these cellular factors.

Adenovirus E1A Proteins↗
PubMed1995

Organization of the human N-acetylglucosaminyltransferase V gene.

UDP-N-acetylglucosamine: alpha-6-D-mannoside beta-1,6-N-acetylglucosaminyltransferase V (GlcNAc transferase V), which catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to alpha-6-D-mannoside, is an important enzyme regulating the branch formation in complex-type, N-linked oligosaccharides. It has been reported that the enzymic activity of GlcNAc transferase V increases after viral transformation and the enzymic product is closely related to the metastasis of tumors. We previously reported the purification, cDNA cloning and chromosomal mapping of human GlcNAc transferase V. In this study, we describe the isolation of genomic clones encoding human GlcNAc transferase V and the structure of the gene. The human GlcNAc transferase V gene is divided into 17 exons, and the open reading frame is encoded by exons 2-17, spanning 155 kb. Analysis of the 5'-untranslated regions of mRNAs from various cells showed multiple sequences depending on the cell types. The promoter region of the GlcNAc transferase V gene was characterized by searching for any consensus sequences matching those for transcription-factor binding. The consensus sequences for a TATA box, AP-1, AP-2, and some other transcription factors were found in the 5'-upstream region of exon 1, and consensus sequences for LF-A1, HNF1-HP1, liver-restricted transcription factors and other factors were also found in intron 1. Chloramphenicol acetyltransferase fusion plasmids with either the 5'-upstream region of exon 1 or intron 1 were constructed and transfected into COS-1 cells. Promoter activities of both DNA fragments were detected, indicating that transcription starts within this region. These data suggest that the human GlcNAc transferase V gene employs a multiple promoter system for its transcription, and gene expression may therefore be regulated in tissue-specific and cell-type-specific manners.

Base Sequence↗
PubMed1995

Suppression of lung metastasis of B16 mouse melanoma by N-acetylglucosaminyltransferase III gene transfection.

The beta 1-6 structure of N-linked oligosaccharides, formed by beta-1,6-N-acetylglucosaminyltransferase (GnT-V), is associated with metastatic potential. We established a highly metastatic subclone, B16-hm, from low metastatic B16-F1 murine melanoma cells. The gene encoding beta-1,4-N-acetylglucosaminyltransferase (GnT-III) was introduced into the B16-hm cells, and three clones that stably expressed high GnT-III activity were obtained. In these transfectants, the affinity to leukoagglutinating phytohemagglutinin was reduced, whereas the binding to erythroagglutinating phytohemagglutinin was increased, indicating that the level of beta 1-6 structure was decreased due to competition for substrate between intrinsic GnT-V and ectopically expressed GnT-III. Lung metastasis after intravenous injection of the transfectants into syngeneic and nude mice was significantly suppressed, suggesting that the decrease in beta 1-6 structure suppressed metastasis via a mechanism independent of the murine system. These transfectants also displayed decreased invasiveness into Matrigel and inhibited cell attachment to collagen and laminin. Cell growth was not affected. Our results demonstrate a causative role for beta 1-6 branches in invasion and cell attachment in the extravasation stage of metastasis.

Agglutination↗
PubMed1995

Transforming growth factor beta up-regulates expression of the N-acetylglucosaminyltransferase V gene in mouse melanoma cells.

beta-1,6-N-acetylglucosaminyltransferase V (GnT-V) (EC 2.4.1.155) that catalyzes beta-1,6 branching in asparagine-linked oligosaccharides is activated on viral or oncogenic transformation and is associated with tumor metastasis. To study the molecular mechanisms involved in regulation of expression of the GnT-V gene, we cloned cDNA and genomic DNA for the enzyme (Saito, H., Nishikawa, A., Gu, J., Ihara, Y., Soejima, Y., Sekiya, C., Niikawa, N., and Taniguchi, N. (1994) Biochem. Biophys. Res. Commun. 198, 318-327). We found that transforming growth factor beta (TGF beta) specifically induced GnT-V expression in mouse melanoma cells. The activity of GnT-V was increased 24 h after the addition of TGF beta and remained at high levels up to 72 h. Northern blot analysis showed that the mRNA levels of GnT-V were consistent with the increased activity. To further investigate the nature of the induction, mRNA stability and transcriptional activity were assayed. The enhancement of the GnT-V mRNA expression resulted from prolonged mRNA stability, not from increased transcription. Consequently, elevated mRNA levels were observed even 72 h after the addition of TGF beta. Lectin blot analysis involving leukoagglutinin showed newly synthesized beta-1,6 branching structures in the sugar chains of a protein of approximately 130 kDa at 48 h after TGF beta treatment. These results suggested that TGF beta caused changes in the sugar chains of proteins in melanoma cells by up-regulating GnT-V expression.

Animals↗
PubMed1995

[The influences of local anesthetics on ryanodine-induced contracture in rat skeletal muscle].

One hundred and fifty paired extensor long digital muscles were excised from Wistar rats and each muscle was prepared in Krebs-Ringer's solution (K-R solution) then gassed with a mixture of 95% O2-5% CO2. The medium for the control muscles was replaced with K-R solution containing 10(-6) M ryanodine and that for the experimental muscles was replaced with medium containing 10(-6) M ryanodine and local anesthetic (LA) (procaine, tetracaine, benzocaine, lidocaine or bupivacaine at various concentration). Isometric contracture tension was recorded throughout the experiment. The ratios of the maximal contracture tension (C-ratio) and the elapsed time (T-ratio) of the muscles treated with LA compared to those of control muscles were calculated. Tetracaine (0.125-1.0 mM) specifically reduced the C-ratio. Procaine (0.5-1.0 mM) and tetracaine (10-60 microM) increased the T-ratio. Procaine (8-16 mM), benzocaine (4-8 mM), lidocaine (0.5-4 mM) and bupivacaine (0.125-1 mM) reduced the T-ratio. The influences of LAs on ryanodine-induced contracture could be explained in terms of their effects on the Ca(2+)-induced Ca2+ release mechanism, direct Ca2+ efflux from sarcoplasmic reticulum (SR), activity of Ca2+ uptake into SR and ryanodine-receptor binding. The complexity of LA effects on ryanodine-induced contracture will affect the results of ryanodine contracture tests for malignant hyperthermia when the muscle specimen is excised under local anesthesia.

Anesthetics, Local↗
PubMed1995

High expression of UDP-N-acetylglucosamine: beta-D mannoside beta-1,4-N-acetylglucosaminyltransferase III (GnT-III) in chronic myelogenous leukemia in blast crisis.

The activity and mRNA expression of UDP-N-acetylglucosamine: beta-D mannoside beta-1,4-N-acetylglucosaminyl transferase III (GnT-III: EC 2.4.1.144) were investigated in hematological malignancies. GnT-III activity was elevated in patients with chronic myelogenous leukemia (CML) in blast crisis and patients with multiple myeloma (MM), as compared to normal healthy subjects and patients with other hematological malignancies including CML in chronic phase. The GnT-III transcript was the same size in leukemic cells from various hematological diseases and cell lines, while expression of the transcript was not found to correlate significantly with enzyme activity, implying that post-translational modification might regulate the activity of GnT-III. Southern-blot analysis showed no significant variation in the structure and position of the GnT-III genome, indicating that the gene is present as a single copy without isoforms. Furthermore, analyses by immunoprecipitation and Western blot revealed that high GnT-III activity in KU812 cell, a CML cell line, resulted in an increase in E4-PHA binding to CD45, a major surface glycoprotein of the leukocyte, indicating that more bisecting GlcNAc was added to CD45 catalyzed by elevated GnT-III.

Acetylglucosamine↗
PubMed1995

Cell spreading in Colo 201 by staurosporin is alpha 3 beta 1 integrin-mediated with tyrosine phosphorylation of Src and tensin.

Staurosporin, a broad-spectrum kinase inhibitor, induced cell spreading in a human colon cancer cell line, Colo 201. On collagen and laminin, cell spreading was induced in more than 90% of the cells and was dependent on very late activation antigen-3, as shown by an antibody inhibition assay. Cell spreading required divalent cations and showed the order of preference Mn2+ > Mg2+ > Ca2+. On fibronectin, only about 30% of the cells were observed to spread, and spreading occurred via a non-integrin, RGD-independent pathway. Staurosporin-induced spreading was inhibited by treatment with tyrosine kinase inhibitors herbimycin A and methyl 2,5-dihydroxycinnamate. Despite the presence of staurosporin, seven proteins (220, 175, 150, 98, 62, 58, and 45 kDa) showed increased levels of tyrosine phosphorylation in association with cell adhesion. Two of these (58 and 220 kDa) were identified by immunoprecipitation as Src product and tensin, respectively. Flow cytometric analysis showed that the Colo 201 cells expressed the alpha 2, alpha 3, alpha 6, and beta 1 chains of integrin, but expression of these chains was not influenced by staurosporin. Immunofluorescence microscopy revealed that the alpha 3 chain, diffusely expressed on the cell surface in the absence of staurosporin, was concentrated at focal adhesion plaques after staurosporin treatment. Neither alpha 2 nor alpha 6 was focalized by the treatment.

Alkaloids↗
PubMed1995

Nucleolar segregation as an early marker for DNA damage; an experimental study in rats treated with 4-hydroxyaminoquinoline 1-oxide.

Male 6-week-old Sprague Dawley rats were given a single intravenous injection of 4-hydroxyaminoquinoline 1-oxide (4HAQO) at a dose of 20 mg/kg in order to produce ultrastructural changes as possible morphological biomarkers for toxicity. Immunohistochemically demonstrated formation of 4HAQO-DNA adduct was correlated with the changes found. Nucleolar alteration, demonstrable by electron microscopy as segregation of nucleolar components into granular and fibrillar compartments, was evident in cells of the target organs, exocrine pancreas and adrenocortex, but not of the non-target liver parenchyma. Sequential observation clarified that such alteration was highest in frequency 6 h and 4 h after 4HAQO administration in pancreatic acinar cells and adrenocortical cells respectively. Electron microscopically, apoptotic changes of acinar cells were evident 2 h after injection of 4HAQO. DNA adduct formation was consistently demonstrated in the same target organs showing nucleolar segregation, the highest frequency being noted 4 h after 4HAQO treatment in both pancreatic acinar cells and adrenocortical cells. Our results thus indicate an identity of the target cells for nucleolar segregation and 4HAQO-DNA adduct formation which correlates with 4HAQO-toxicity. We suggest that nucleolar segregation occurs subsequent to the generation of DNA damage.

4-Hydroxyaminoquinoline-1-oxide↗
PubMed1995

Effects of dibutyryl cAMP and bromodeoxyuridine on expression of N-acetylglucosaminyltransferases III and V in GOTO neuroblastoma cells.

The sugar chain structures of the cell surface change dramatically during cellular differentiation. A human neuroblastoma cell line, GOTO, is known to differentiate into neuronal cells and Schwannian cell-like cells on treatments with dibutyryl cAMP and bromodeoxyuridine, respectively. We have examined the expression of UDP-N-acetylglucosamine: beta-D-mannoside beta-1,4N-acetylglucosaminyltransferase III (GnT-III: EC 2.4.1.144) and UDP-N-acetylglucosamine: alpha-6-D-mannoside beta-1,6N-acetylglucosaminyltransferase V (GnT-V: EC 2.4.1.155), two major branch forming enzymes in N-glycan synthesis, in GOTO cells on two distinct directions of differentiation. In neuronal cell differentiation, GnT-III activity showed a slight increase during initial treatment with Bt2cAMP for 4 days and decreased drastically after the fourth day, but the mRNA level of GnT-III did not show a decrease but in fact a slight increase. GnT-V activity increased to approximately two- to three-fold the initial level with increasing mRNA level after 8 days, and lectin blot analysis showed an increase in reactivity to Datsura stramonium (DSA) of the immunoprecipitated neural cell adhesion molecule (NCAM). In Schwannian cell differentiation, the activity and mRNA level of GnT-III showed no significant change on treatment with BrdU. GnT-V activity also showed no change in spite of the gradual increase in the mRNA level. These results suggest that the activation of GnT-V during neuronal cell differentiation of GOTO cells might be a specific change for branch formation in N-glycans, and this affects the sugar chain structures of some glycoproteins such as NCAM.

Bromodeoxyuridine↗
PubMed1995

Effect of cigarette smoke on the mutagenic activation of various carcinogens in hamster.

Male Syrian golden hamsters were exposed for 1 or 2 weeks to smoke produced by commercial non-filter cigarettes for 5 consecutive days in a Hamburg type II smoking machine. Postmitochondrial fractions (S9) prepared from the liver, lungs, and pancreas were used in the Ames liquid incubation assay, in order to assess the effect of cigarette smoke (CS) on the metabolic activation of four groups of procarcinogens. The mutagenic activities of five heterocyclic amines on strain TA98 in the presence of liver S9 mix were induced up to 3.7 times above controls including sham smoke control, while no significant alteration of mutagenicity was observed with 3'-hydroxymethyl-N,N-dimethyl-4-aminoazobenzene and benzo[a]pyrene on TA98 or with N-nirosobis(2-oxopropyl)amine (BOP) on TA100. A similar stimulation of metabolic activation was also observed for 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) with S9 from the lungs but not from the pancreas. The mutagenic potential of 11 carcinogens including aflatoxin B1 (AFB1) and two other heterocyclic amines was also examined using liver S9 from male hamsters pretreated with phenobarbital (PB) or 3-methylcholanthrene (MC). The numbers of revertant colonies were much higher (2-20-fold) in the presence of MC-treated liver S9 than in the presence of PB-treated liver S9, except in the case of AFB1 which showed a higher mutagenicity with PB-induced S9. 7,8-Benzoflavone considerably inhibited the activities of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and Trp-P-1 in the presence of either untreated, MC- or CS-treated liver S9, whereas metyrapone was totally lacking this effect, indicating that cytochrome P450(CYP)1A1/1A2 isoforms of hamster liver are predominantly involved in the metabolic activation of these carcinogens. CS exposure of hamsters might selectively induce hepatic CYP1A2 which cannot activate BOP. Consequently, the present findings could explain, in part, the anticarcinogenic effect of CS on BOP-induced pancreatic tumors in hamsters. The findings further support the idea that CS markedly stimulates the metabolic activation of food-derived carcinogens, which may contribute to the overall carcinogenic effects of cigarette smoking.

Animals↗