Biomedical subjects

S De Flora

Publications and source records attributed to S De Flora.

At least 127 records · Page 7Linked to original sources

PubMed1986

Inhibition of urethan-induced lung tumors in mice by dietary N-acetylcysteine.

The thiol N-acetylcysteine (NAC), a precursor of intracellular glutathione (GSH), efficiently prevented the induction of lung tumors in Swiss albino mice, when supplemented to the diet (0.2%) both before and after an i.p. injection of the carcinogen urethan (ethyl carbamate). Irrespective of urethan administration, NAC also significantly enhanced GSH S-transferase activity in liver preparations of the same animals. These data show that, under certain conditions, it is possible to prevent chemically induced cancer by increasing the levels of physiological trapping agents.

Acetylcysteine↗

PubMed1986

Bacterial genotoxicity of nitrosated famotidine.

Famotidine, a histamine H2-receptor antagonist, was devoid of mutagenic activity in seven his- Salmonella typhimurium strains (TA1535, TA1537, TA1538, TA97, TA98, TA100 and TA102) and was equitoxic in repair-proficient (WP2) and repair-deficient (WP2uvrA, WP67, CM561, CM571, WP100 and CM871) Escherichia coli strains, both in the presence and in the absence of S9 mix containing liver S9 fractions from Aroclor-treated rats. However, after a short pre-incubation step with nitrite in an acidic environment, the drug increased, by a direct mechanism, the number of his+ revertants in Salmonella strains TA100, TA102 and TA97 (a decrease of mutagenicity being conversely observed in TA1535) and of trp+ revertants in E. coli strains WP2uvrA and WP67. Moreover, it enhanced the induction of non-reparable DNA damage in E. coli strains simultaneously lacking the uvrA-dependent excision repair and the lexA post-replication repair pathways. The mutagenicity of acidified nitrite-famotidine mixtures was related to doses of both precursors, with a maximum production of mutagenic derivatives in a slight molar excess of nitrite. The optimal pH of the nitrosation reaction (2.0) was intermediate between the one required for cimetidine (1.5) and ranitidine (2.5). Potency of famotidine as a precursor of mutagenic derivatives was considerably lower than the one of the other two H2 blockers. The nitrosation products of all three drugs mainly induced base-pair substitutions in Salmonella DNA, to a greater extent at sites containing G.C base pairs (strain TA100) in the case of famotidine and cimetidine, and at sites containing A.T base pairs (TA102) in the case of ranitidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Metabolic, desmutagenic and anticarcinogenic effects of N-acetylcysteine.

N-acetylcysteine (NAC) is often administered to respiratory patients with histories of exposure to noxious agents (e.g. cigarette smoke and atmospheric pollutants), which are known to act as glutathione (GSH) depletors and as cancer initiators and/or promoters. Since NAC is a precursor of intracellular GSH, we investigated its effects on GSH metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds. In vitro, NAC induced a significant increase in oxidized glutathione (GSSG) reductase activity in rat liver preparations and counteracted the mutagenicity of direct-acting compounds (such as epichlorohydrin, hydrogen peroxide, 4-nitroquinoline-N-oxide and dichromate), as a result of its reducing and scavenging properties. At high concentrations, the drug completely inhibited the mutagenicity of procarcinogens (cigarette smoke condensate, tryptophan pyrolysate, cyclophosphamide, 2-aminofluorene, benzo(a)pyrene and aflatoxin B1) by binding their electrophilic metabolites. In contrast, their metabolic activation was stimulated by decreasing NAC concentrations, especially when liver preparations from enzyme-induced rats were used. Lung and liver subcellular preparations of rats treated in vivo with NAC, in various combinations with enzyme inducers and/or GSH depletors, also affected the mutagenicity of a number of compounds. NAC generally increased intracellular GSH and restored its levels following depletion. It did not affect the levels nor the spectral properties of cytochromes P-450 in pulmonary and hepatic microsomes, whereas it stimulated, especially in Aroclor-pretreated animals, cytosolic enzyme activities involved in NADP or GSSG reduction (G6PD, 6PGD and GSSG reductase) and in the reductive detoxification of xenobiotics (DT diaphorase). When administered with the diet, at a nontoxic posology (120 mg/kg b.w.), NAC markedly inhibited the induction of lung tumors in mice by a potent carcinogen (urethane).

Acetylcysteine↗

PubMed1986

Metabolic reduction of chromium by alveolar macrophages and its relationships to cigarette smoke.

Pulmonary alveolar macrophages (PAM), obtained by bronchoalveolar lavage from 47 individuals, reduced hexavalent chromium [Cr(VI)] and decreased its mutagenicity. Their specific activity--mostly mediated by cytosolic, enzyme-catalyzed mechanisms--was significantly higher than in corresponding preparations of mixed-cell populations from human peripheral lung parenchyma or bronchial tree, or from rat lung or liver. At equivalent number of PAM, Cr(VI) reduction, total protein, and some oxidoreductase activities were significantly increased in smokers. No appreciable variation could be detected between lung cancer and noncancer patients. In rats, the Cr(VI)-reducing activity of PAM preparations was induced by Aroclor 1254. Thus, alveolar macrophages provide crucial defense mechanisms not only by phagocytizing metals, but also by metabolically reducing Cr(VI). The epithelial-lining fluid (ELF) also displayed some Cr(VI) reduction. Together with already investigated metabolic processes occurring inside lung cells, these mechanisms are expected to determine thresholds in the pulmonary carcinogenicity of chromium.

Animals↗

PubMed1985

Metabolic activation of hepatocarcinogens in chronic hepatitis B.

S9 fraction pools of liver biopsy samples, collected from 129 patients in two consecutive studies, were comparatively assayed for their ability to activate aflatoxin B1 (AFB1) and a tryptophan pyrolysate product (Trp-P-2) in a miniaturized Salmonella mutagenicity test system. Metabolic activation was not affected to a significant extent by most of the monitored variability factors, such as sex, alcohol, cigarette smoking and liver histology (minimal changes, chronic persistent (CPH) or active (CAH) hepatitis, CAH steatosis, or cirrhosis). Conversely, a significant enhancement of activation was observed for AFB1 in cases of mild CAH and especially for Trp-P-2 in hepatitis B virus carriers, irrespective of their histologic diagnosis.

Aflatoxin B1↗

PubMed1985

Assay of phenacetin genotoxicity using in vitro and in vivo test systems.

Phenacetin was assayed in a battery of five short-term tests. (1) In a DNA-repair test using various Escherichia coli strains, the drug was not directly genotoxic nor did it induce nonreparable DNA damage in the presence of rat liver S9 fractions, while it was weakly active following activation with hamster liver S9. (2) In the Ames reversion test (strains TA97, TA98, TA100, and TA102 of Salmonella typhimurium, phenacetin reverted only TA100, and only in the presence of hamster liver S9. Mutagenicity was related to the concentration both of the drug and of the above metabolic system. There was no activation with hamster kidney S9, uninduced chicken liver S9, or with a variety of liver S9 preparations from rats treated with enzyme inducers (Aroclor 1254, phenobarbital, or 3-methylcholanthrene) and/or glutathione depletors (diethyl maleate or buthionine sulfoximine). Hamster liver S9 compared favorably to rat and even more to chicken liver S9 fractions also in activating various promutagens [3-amino-1-methyl-SH-pyrido (4,3-b)-indole, 2-aminofluorene, aflatoxin B1, benzo[a]pyrene, and benzo[a]pyrene-trans-7,8-diol] and in decreasing the mutagenicity of direct-acting compounds (4-nitroquinoline N-oxide and sodium dichromate). (3) Phenacetin was borderline positive in a forward mutation test (6-thioguanine resistance) in V79 cells, only in the presence of hamster liver S9, and gave negative results in the presence of rat liver S9 or without any metabolic system. (4) Following in vivo treatment, the alkaline elution assay did not reveal any DNA fragmentation in bone-marrow cells of ip-treated mice or in liver cells of rats treated by gavage. Apparent DNA damage was instead observed in the kidneys of rats receiving the drug by gavage or in the liver following ip administration. However, the effect was prevented (liver) or reduced (kidney) by preliminary perfusion of the organs, which discards (liver) or makes uncertain (kidney) the hypothesis of a true in vivo DNA damage. (5) Phenacetin ip induced in mouse bone-marrow cells a poor yet statistically significant increase in sister chromatid exchanges.

Animals↗

PubMed1985

In vivo effects of N-acetylcysteine on glutathione metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds.

N-acetylcysteine (NAC) was administered to rats in various combinations with an enzyme inducer (Aroclor 1254) and with depletors of reduced glutathione (GSH), i.e., diethyl maleate (DEM) and buthionine sulfoximine (BSO). NAC increased intracellular glutathione levels in erythrocytes and in liver and lung cells, and replenished its stores following depletion. It did not affect the concentrations nor the spectral properties of cytochromes P-450 in hepatic and pulmonary microsomes, whereas it stimulated, especially in Aroclor-pre-treated animals, cytosolic enzyme activities involved in NADP reduction (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase), in glutathione reduction (GSSG-reductase) and in the reductive detoxication of xenobiotics by-passing formation of reactive oxygen species (DT-diaphorase). In vivo treatment with the drug enhanced detoxication by liver and lung S-12 fractions of direct-acting mutagens (ICR 191, epichlorohydrin, 4-nitroquinolino-N-oxide and dichromate) and counteracted opposite effects triggered by administration of GSH depletors. The metabolic activation of procarcinogens (aflatoxin B1, 2-aminofluorene, cyclophosphamide, benzo[a]pyrene, a tryptophan pyrolysate product and cigarette smoke condensate) was inhibited by NAC in uninduced rats, while it was further stimulated in Aroclor-pre-treated animals. Additional assays, performed also with other enzyme inducers (phenobarbital and 3-methylcholanthrene) suggested that the effect of NAC on the metabolic activation of procarcinogens depends on the balance between an increased production of mutagenic metabolites (prevailing in induced animals) and their binding by intracellular thiols (prevailing under normal conditions). Thus, due to its dual role as a nucleophile and as a SH donor, NAC appears to exert protective effects by modulating glutathione metabolism and the biotransformation of mutagenic/carcinogenic compounds. This may have clinical relevance, since NAC is administered to individuals, such as cigarette smokers, who are more heavily exposed to GSH depletors and to carcinogenic agents.

Acetylcysteine↗

PubMed1985

Specificity and inducibility of the metabolic reduction of chromium(VI) mutagenicity by subcellular fractions of rat tissues.

The mutagenicity of sodium dichromate in the Ames test was decreased as a consequence of chromium(VI) reduction by tissue postmitochondrial (S-9 or S-12) fractions from untreated rats with the following rank of efficiency: liver; kidney; and lung. The effects of lung preparations were significantly enhanced following the intratracheal administration of high doses (0.25 mg/kg) of dichromate itself, 5 times per week for 4 weeks (i.e., 20 fractionated instillations). No changes were conversely detected following single weekly doses of 1.25 mg/kg for the same period (i.e., four cumulative instillations). The local stimulation of chromium(VI) metabolism was also confirmed by testing the mutagenicity of calcium chromate and chromium trioxide, whereas the metabolism of a number of other activatable or deactivatable mutagens was not significantly affected by intratracheal treatment with chromium(VI). Of three enzyme inducers injected i.p. which modified the spectral properties and/or concentration of cytochromes P-450 in liver and lung microsomes, only Aroclor 1254 proved to stimulate chromium(VI) metabolism in lung cells. In liver cells, Aroclor 1254 and to a lower extent phenobarbital induced chromium(VI) reduction, while 3-methylcholanthrene was ineffective. Pretreatment of rats with these three compounds resulted in a selective induction of the metabolic activation of promutagens [benzo(a)pyrene and its trans-7,8-diol, 2-aminofluorene, aflatoxin B1] and of the metabolic deactivation of direct-acting mutagens [2-methoxy-6-chloro-9-[3-(2-chloroethyl)-aminopropylamino] acridine X 2HCl, epichlorohydrin, 4-nitroquinolino-N-oxide] by S-12 and microsomal fractions. These findings indicate that, in addition to already recognized detoxification mechanisms operating outside target cells (26), specific and inducible chromium-reducing pathways, mediating threshold phenomena in chromium carcinogenesis, do also occur in the intracellular environment.

Animals↗

PubMed1985

Prominent role of DT-diaphorase as a cellular mechanism reducing chromium(VI) and reverting its mutagenicity.

Rat liver postmitochondrial (S-12) fractions accounted for the bulk of the activity of whole cell homogenates in reducing chromium(VI) and accordingly in decreasing its mutagenicity. Both cytosolic (S-105) and microsomal fractions concurred to this process, which in all subcellular preparations tested was selectively induced by phenobarbital and especially by Aroclor 1254, but not by 3-methylcholanthrene. Cytosolic fractions were markedly more efficient in reducing chromium(VI) than microsomal fractions recovered from the same amount of tissue (liver or lung), although the latter preparations had a higher specific activity. The microsomal activity was exclusively NADPH dependent. A minor part of the cytosolic reduction was determined by nonenzymatic components, notably by some electron donors and chiefly by reduced glutathione, which proved to reduce chromium(VI) at physiological concentrations. However, also in cytosolic fractions, the most important contribution to chromium reduction was enzyme catalyzed, as shown by the following properties: thermolability; requirement for exogenous NADH or NADPH [supplied as such or in the form of a NADPH-generating system (S-9 mix)]; and saturation by chromium(VI). The likely involvement of DT-diaphorase in this metabolic process is supported by several findings, including its sharp pH dependence and its partial suppression by known inhibitors of this enzyme protein, such as p-chloromercuribenzoate, L-thyroxine, and dicumarol (which conversely did not counteract the metabolic deactivation of the other direct-acting mutagens 2-methoxy-6-chloro-9-[3-(2-chloroethyl)aminopropylamino]acridine 2HCl and epichlorohydrin). Similarly, cytosolic reduction of chromium(VI) was partially inhibited by selective metabolic depletors of both coenzymes of DT-diaphorase, i.e., NADPH and NADH. Pretreatment of rats with enzyme inducers (phenobarbital and 3-methylcholanthrene) stimulated the activity of DT-diaphorase in liver cytosolic fractions. A dramatic stimulation (35 to 40 times over untreated controls) was produced by Aroclor 1254, which also coinduced the liver cytosolic activity of enzymes involved in the glucose 6-phosphate-dependent pathway of both nicotinamide-adenine-dinucleotide phosphate and glutathione reduction (glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and glutathione reductase). In the lung cytosol, a slight yet significant stimulation of some of these enzyme activities was determined by the daily intratracheal instillations of high doses of chromium(VI) itself for 4 weeks, a condition which has been found to enhance the pulmonary metabolism of this metal ion.

Animals↗

PubMed1984

Genotoxic activity and potency of 135 compounds in the Ames reversion test and in a bacterial DNA-repair test.

Compounds of various chemical classes were comparatively assayed in the Ames reversion test with his- S. typhimurium strains TA1535, TA157 , TA1538, TA98, TA100, and, in part, TA97 , and in a DNA-repair test with trp- E. coli strains WP2 (repair-proficient), WP67 (uvrA- polA-) and CM871 (uvrA- recA- lexA-). A liquid micromethod procedure for the assessment of the minimal inhibitory concentration (MIC) of test compounds, using the same reagents as the Ames test, was set up and calibrated in its technical details. Other techniques (spot test and treat-and-plate method) were applied to a number of compounds in order to obtain more complete information on their DNA-damaging activity in E. coli. From a qualitative standpoint, the results obtained in the reversion test and in the DNA-repair test (liquid micromethod) were overlapping for 96 (59 positive and 37 negative) out of 135 compounds (71.1%). There was disagreement for 39 compounds (28.9%), 9 of which were positive only in the reversion test (8 requiring metabolic activation and 5 genotoxic in the treat-and-plate method). 30 compounds were positive only in the lethality test, showing a direct DNA-damaging activity, which in half of the cases was completely eliminated by S9 mix. Although the experimental protocol intentionally included several compounds already reported as nonmutagenic carcinogens or as noncarcinogenic mutagens, the overall accuracy was 64.5% for the reversion test and 72.4% for the DNA-repair test, as evaluated for 75 compounds classified according to their carcinogenic activity. Quantitation of results was obtained in the Ames test by relating the net number of revertants to nmoles of compound and in the DNA-repair test by means of a formula relating the difference and ratio of MICs in repair-proficient and -deficient bacteria to nmoles of compound. Following these criteria, the genotoxic potency varied over a 4.5 X 10(7)-fold range among compounds positive in the reversion test and over a 6 X 10(9)-fold range among compounds damaging E. coli DNA. The genotoxic potencies in the two bacterial systems were correlated within the majority of the chemical classes under scrutiny.

Biotransformation↗

PubMed1984

Statistical evaluation of inter- and intra-laboratory variations of the Ames test, as related to the genetic stability of Salmonella tester strains.

A statistical analysis was performed on the data resulting from an international collaborative study of the Ames test according to a standardized experimental protocol, which involved the comparative testing of 4NQO (4 doses), in 3 separate experiments for each of the 38 participating laboratories, by using a common reference (R) culture and in-house laboratory (L) cultures of 5 strains of S. typhimurium. Despite some toxicity phenomena recorded at the highest dose of 4NQO, the majority of the dose-response curves in individual laboratories were linear on a bi-log scale and their mean values fitted a linear regression framework. Scattering of data around mean values of laboratories was Gaussian-like even at the highest dose of 4NQO, toxic effects being expressed as a dose-related increase of variance. A weighted least-square analysis could therefore take into account toxic effects without resorting to a sophisticated non-linear model incompatible with log transformation. Various analytical approaches--e.g. the weighted estimates of linear regression parameters, a multifactor (laboratory, experiment, dose, culture of each strain) analysis of variance with all the possible interactions, the assessment of correlations in individual laboratories and of coefficients of variation for induced and spontaneous mutability--could detect some statistically significant differences between L and R cultures. However, at a critical evaluation on an individual basis, only few of these differences, without any peculiar involvement of given strains, were convincing in view of the existence of real phenomena of genetic drift. Therefore, on the whole, the genetic drift of Salmonella tester strains appears to lend a negligible contribution to the considerable inter- and intra-laboratory variability detected in this study. With a background variability between replications averaging 26%, a dose-related variability was evident both between experiments (28-54%) and between laboratories (44-127%).

4-Nitroquinoline-1-oxide↗

PubMed1984

Metabolic activation and deactivation of mutagens by preparations of human lung parenchyma and bronchial tree.

69 S12 preparations of human lung (43 of peripheral lung parenchyma and 26 bronchial preparations) were assayed for their ability to activate procarcinogens to mutagenic metabolites in the Ames test or to lower the mutagenic response of direct-acting compounds. No sample activated polycyclic aromatic hydrocarbons, such as 3-methylcholanthrene, benzo[a]pyrene or its metabolites 3-hydroxy-B(a)P and B(a)P-trans-7,8-diol, and only borderline effects were observed with cigarette-smoke condensates. Conversely, some activating ability was detected in the case of 2-aminofluorene and of cyclophosphamide. The same samples produced a slight decrease of mutagenicity of epichlorohydrin and ICR-191 and a more pronounced loss of activity of sodium dichromate and 4-nitroquinoline N-oxide.

Biotransformation↗

PubMed1984

In vitro effects of N-acetylcysteine on the mutagenicity of direct-acting compounds and procarcinogens.

N-Acetylcysteine (NAC), reduced (GSH) and oxidized (GSSG) glutathione were negative in the Ames test with 7 Salmonella strains, while L-cysteine was activated by rat liver S-9 fractions to metabolites mutagenic to strains TA102, TA97 and TA100. The mutagenic response in S. typhimurium strains (TA1535, TA98, TA100, TA102) and the levels of enzyme activities, responsible for NADP+ or GSSG reduction and for the utilization of NADPH or GSH in rat liver S-9 fractions, were investigated following in vitro preincubation of NAC with four direct-acting mutagens and six procarcinogens. Treatment with this nucleophilic and reducing compound resulted in a dose-related decrease of the direct mutagenicity of epichlorohydrin, hydrogen peroxide and, sharply, of 4-nitroquinolino-N-oxide and sodium dichromate. The mutagenicity of these compounds, both in the absence and in the presence of NAC, was decreased by rat liver S-9 fractions and to some extent by lung S-9 fractions. A diphasic effect was observed in the case of procarcinogens (cyclophosphamide, 2-aminofluorene, cigarette smoke condensate, Trp-P-2, aflatoxin B1 and benzo[a]pyrene), i.e., an enhancement of S-9 requiring mutagenicity at intermediate NAC doses, which could be ascribed to metabolic factors acting in vitro, and a loss of mutagenicity at high NAC doses, which could be ascribed to trapping of electrophilic metabolites. Out of the five S-9 enzyme activities under study, i.e., glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, malic enzyme, GSH peroxidase and GSSG reductase, only the last one showed significant changes following mutagen and/or NAC treatment.

Acetylcysteine↗

PubMed1984

Detoxification of genotoxic compounds as a threshold mechanism limiting their carcinogenicity.

In vitro metabolic trends were assessed for 100 genotoxic agents detected in two bacterial test systems, i.e., the Ames reversion test and a liquid DNA-repair test in Escherichia coli. Seventy-five compounds were found to undergo a more or less pronounced decrease of genotoxicity, in at least one of these models, in the presence of rat liver homogenates or in other metabolic systems (up to 40 different preparations, from various sources, for chromium compounds). A number of these deactivable compounds are reported in the literature to yield negative or equivocal results in animal carcinogenicity assays, which may imply the existence of metabolically regulated thresholds in the initiation of cancer. Several examples are provided to support this hypothesis. The in vitro treatment with a pharmacologic agent (N-acetylcysteine) enhanced detoxification mechanisms, either by stimulating enzyme activities promoting glutathione formation in liver homogenates or by reacting itself with direct-acting mutagens and with the genotoxic metabolites of procarcinogens.

Aflatoxin B1↗

PubMed1983

High sensitivity of Salmonella TA102 in detecting hexavalent chromium mutagenicity and its reversal by liver and lung preparations.

The recently developed strain TA102, particularly suited to the detection of oxidative mutagens (Levin et al., 1983), was the most sensitive out of 9 strains of S. typhimurium his- in revealing the mutagenicity of Cr(VI) compounds (sodium dichromate, calcium chromate and chromium trioxide). The rank of sensitivity was the following: TA102, TA100, TA97, TA92, TA1978, TA98, TA1538 and TA1537, TA1535 being the only insensitive strain. Cr(III) compounds (chromic acetate, chromic nitrate and chromic potassium sulfate) were totally inactive with all strains. The direct mutagenicity of Cr(VI) was markedly decreased, through NADPH-requiring mechanisms, by rat-liver S9 fractions and, to a lower extent, by human lung S12 fractions, which supports the hypothesis of a metabolically regulated threshold in chromium pulmonary carcinogenicity.

Animals↗

PubMed1983

Mutagenic and DNA damaging activity in muscle of trout exposed in vivo to nitrite.

Muscle ether extracts of rainbow trout (Salmo gairdneri) exposed to lake water enriched with nitrite (450 micrograms/l) reverted plasmid-containing his- strains of Salmonella typhimurium, mainly eliciting frameshift mutations, and induced a DNA damage in Escherichia coli reparable through the recA/lexA-dependent SOS functions. The number of revertants was related to their content in nitroso-derivatives and to the physiological condition of the fish. Mutagenicity was efficiently decreased, through NADPH-requiring pathways, by liver S-9 fractions from rats or rainbow trout, while it was not affected by preliminary heating nor by pre-incubation with human gastric juice.

Animals↗

PubMed1983

Genotoxicity of nitrosated ranitidine.

The in vitro reaction of nitrite with the histamine H2-receptor antagonist ranitidine, in acidified solutions or in human gastric juice, resulted in the formation of genotoxic derivatives, mainly eliciting base-pair substitutions in his-Salmonella typhimurium and trp- Escherichia coli and inducing an increased lethality in DNA repair-deficient bacteria. The mutagenic response was better expressed in the presence of rodent (rat, mouse) and even more of human liver preparations. The patterns of this reaction, e.g., the optimal pH, temperature and time of preincubation, doses of precursor compounds, effect of inhibitors (ascorbic acid), the genotoxic mechanisms and in vitro metabolic trends were investigated and compared with those resulting from nitrosation of cimetidine under the same experimental conditions. Although the reaction proceeded under conditions simulating the gastric environment, an excess of nitrite was needed, in the case of ranitidine, for optimal formation of mutagenic derivatives. Gastric juice samples from fasting individuals treated with ranitidine were devoid of mutagenic activity, and the addition of nitrite to these samples was also without a reproducible effect. Conversely, under the same conditions, most samples from both untreated and ranitidine-treated individuals induced mutations of different genetic specificity (frameshift errors), resulting from nitrosation of physiological components of gastric juice.

Animals↗

PubMed1982

Genotoxic activity of five antidepressant hydrazines in a battery of in vivo and in vitro short-term tests.

Five antidepressant agents (monoamine oxidase inhibitors) having a hydrazino group--phenelzine, nialamide, mebanazine, isocarboxazid, and iproniazid--were assayed in four in vivo or in vitro short-term tests predictive of the potential carcinogenicity of chemicals. (1) All the compounds tested except iproniazid, produced DNA fragmentation, as evaluated by the alkaline elution technique, in liver and/or lung cells of mice treated ip or po. (2) All the compounds except mebanazine (which was no longer available for testing) were weak inducers of sister chromatid exchanges in bone marrow cells of mice treated ip. (3) Phenelzine and nialamide elicited base-pair substitutions and mebanazine elicited frameshift errors in his- Salmonella typhimurium. S9 mix containing rat liver, mouse liver, or mouse lung S9 fractions had variable effects on mutagenicity. (4) The same three compounds were positive in a DNA repair bacterial test with five trp- Escherichia coli strains lacking a variety of repair mechanisms (uvrA, polA, recA, lexA) or incorporating plasmids (R391).

Animals↗