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J K Hongslo

Publications and source records attributed to J K Hongslo.

At least 19 recordsLinked to original sources
PubMed1998

Single-strand breaks, cell cycle arrest and apoptosis in HL-60 and LLCPK1 cells exposed to 1,2-dibromo-3-chloropropane.

We investigated 1,2-dibromo-3-chloropropane (DBCP)-induced DNA damage, cell cycle alterations and cell death in two cell lines, the human leukemia HL-60 and the pig kidney LLCPK1, both of which are derived from potential target sites for DBCP-induced toxicity. DBCP (30-300 micromol/L) caused a concentration-dependent increase in the levels of DNA single-strand breaks in both cell lines as well as in cultured human renal proximal tubular cells. After extended DBCP exposure in LLCPK1 cells (100 micromol/L, 30 h), the level of DNA breaks returned almost to control values. Incubation for 48 h showed a clear reduction of growth with DBCP concentrations as low as 10 micromol/L. Flow cytometric analysis showed that DBCP (1-10 micromol/L) exposure for 24 h caused an accumulation of LLCPK1 cells in the G2/M-phase. In HL-60 cells the accumulation in G2/M-phase was less marked, and at higher concentrations the cells accumulated in S-phase. Flow cytometric studies of HL-60 and LLCPK1 cells exposed to 100-500 micromol/L DBCP showed increased number of apoptotic cells/bodies with a lower DNA content than that of the G1 cells. Microscopic studies revealed that there were increased numbers of cells with nuclear condensation and fragmentation, indicating that apoptosis was the dominant mode of death in these cell lines, following exposure to DBCP. The characteristic ladder pattern of apoptotic cells was observed when DNA from DBCP-treated HL-60 cells and LLCPK1 cells was electrophoresed in agarose. The finding that DBCP can cause an accumulation of cells in G2/M-phase and induce apoptosis in vitro may be of importance for the development of DBCP-induced toxicity in vivo.

Animals↗
PubMed1997

Apoptosis in HL-60 cells induced by 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX).

The potent bacterial mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX), which is formed during chlorination of drinking water, has been studied with respect to induction of cell death in promyelocytic leukemic HL-60 cells. Cells exposed to MX for 1 h and further incubated for 3 h, revealed no significant increase in the proportion of cells with compromised plasma membrane damage as judged by trypan blue or propidium iodide exclusion. However, flow cytometric studies and microscopic analysis of HL-60 cells after staining with Giemsa or Hoechst 33342, revealed that more than 30% of the cells exposed to 30-100 microM of MX, showed the characteristic morphology and biochemical markers of apoptosis. On the other hand, in cultures exposed to 300 microM MX, less than 5% of the cells appeared to be apoptotic (< G1 DNA) 3 h after treatment, which is similar to control values. Microscopic analysis of Hoechst 33342-stained cells revealed that they were 'arrested' in the early stages of chromatin condensation, but these cells eventually became necrotic. Some decrease in the percentage of cells in S-phase was observed 3 h after exposure to MX (10, 30 and 100 microM), but the induced cell death was not markedly cell stage specific. The characteristic ladder pattern of apoptotic cells was observed when DNA isolated from MX-exposed HL-60 cells was electrophoresed in agarose. The apoptotic process could also be detected by analysis with alkaline filter elution (AE), as a decrease in the total DNA recovered; and by single cell gel electrophoresis, as a decrease in the average number of cells/comets observable on each slide. With the protocols used no apparent increase in values in the normalized area above the curve (NAAC) (alkaline elution) or tail moments (single cell gel electrophoresis (SCGE)) were detected, indicating that apoptotic cells are not necessarily a confounding factor when assaying for genotoxicity with these techniques.

Adult↗
PubMed1997

Paracetamol inhibits cell cycling and induces apoptosis in HL-60 cells.

We investigated the effects of paracetamol on cell cycle and cell death in cultured HL-60 cells. Paracetamol (0.1-3.0 mM) caused a dose-dependent inhibition of cell proliferation. Inhibition of DNA synthesis was observed at as low concentrations as 0.03 mM. When HL-60 cells were exposed to paracetamol (0.1-1.0 mM), flow cytometric analysis showed that cells accumulated in the G1/S phase, and then slowly proceeded through the S-phase. Exposure to 2.0-3.0 mM paracetamol, on the other hand, resulted in a reduction of the number of cells in S-phase and G2/M phase, and a concurrent increase in cells/bodies with a lower DNA content than that of the G1 cells. Microscopic studies revealed increased numbers of cells with nuclear condensation and fragmentation, indicating that apoptosis was the dominating mode of death in this cell line after exposure to paracetamol. However, when DNA from paracetamol-treated cells were electrophoresed in agarose, no clear ladder pattern characteristic for apoptotic cells was observed. This was most likely a result of secondary necrosis which followed incomplete apoptosis. Within 5-10 hr after start of paracetamol exposure, a marked downregulation of both c-myc and bcl-2 mRNA was observed. In conclusion, the present results show that exposure to high non-therapeutic concentrations of paracetamol cause cell cycle arrest and apoptosis in HL-60 cells in S-phase.

Acetaminophen↗
PubMed1996

Environmental chemicals relevant for respiratory hypersensitivity: the indoor environment.

The allergenic constituents of non-industrial indoor environments are predominantly found in the biologic fraction. Several reports have related biological particles such as mites and their excreta, dander from pets and other furred animals, fungi and bacteria to allergic manifestations including respiratory hypersensitivity among the occupants of buildings. Also, bacterial cell-wall components and the spores of toxin-producing moulds may contribute to the induction of hypersensitivity, but the relevance for human health is not yet determined. The knowledge regarding hypersensitivity and asthmatic reactions after exposure to chemical agents is primarily based on data from occupational settings with much higher exposure levels than usually found in non-industrial indoor environments. However, there is evidence that indoor exposure to tobacco smoke, some volatile organic compounds (VOC) and various combustion products (either by using unvented stoves or from outdoor sources) can be related to asthmatic symptoms. In some susceptible individuals, the development of respiratory hypersensitivity or elicitation of asthmatic symptoms may also be related to the indiscriminate use of different household products followed by exposure to compounds such as diisocyanates, organic acid anhydrides, formaldehyde, styrene and hydroquinone. At present, the contribution of the indoor environment both to the development of respiratory hypersensitivity and for triggering asthmatic symptoms is far from elucidated.

Air Pollution, Indoor↗
PubMed1995

International Commission for Protection against Environmental Mutagens and Carcinogens. An evaluation of the genetic toxicity of paracetamol.

During the last years, several reports have indicated genotoxic effects of paracetamol, a widely used non-prescription analgesic and antipyretic drug. Thus, a careful evaluation of a possible genotoxic effect related to paracetamol use is warranted. Studies in vitro and in vivo indicate that the reactive metabolite of paracetamol can bind irreversibly to DNA and cause DNA strand breaks. Paracetamol inhibits both replicative DNA synthesis and DNA repair synthesis in vitro and in experimental animals. Paracetamol does not cause gene mutations, either in bacteria or in mammalian cells. On the other hand, a co-mutagenic effect of paracetamol has been reported. Furthermore, paracetamol increases the frequency of chromosomal damage in mammalian cell lines, isolated human lymphocytes and experimental animals. Two independent studies have shown an increase in chromosomal damage in lymphocytes of human volunteers after intake of therapeutic doses of paracetamol, whereas a third study was negative. Paracetamol-induced chromosomal damage appears to be caused by an inhibition of ribonucleotide reductase. This indicates that a threshold level for the paracetamol-induced chromosomal damage may exist. Genotoxic effects of paracetamol have, however, been demonstrated both in vitro and in vivo at or near therapeutic concentrations. The data indicate that the use of paracetamol may contribute to an increase in the total burden of genotoxic damage in man. Thus, there may be a need to evaluate the therapeutic benefit of paracetamol, taking into consideration not only its potential to induce acute and chronic organ damage, but also genotoxic effects.

Acetaminophen↗
PubMed1995

Inhibitory effects of paracetamol on DNA repair in mammalian cells.

Paracetamol blocks DNA replication by inhibiting deoxyribonucleotide (dNTP) synthesis and may therefore also interfere with DNA repair. In the present work various mammalian cell types were treated with genotoxic agents and allowed to repair in the presence or absence of paracetamol. Alkaline elution was used to assay DNA single-strand breaks plus alkali-labile sites (= SSBs). Resting human mononuclear blood cells (MNC) exposed to 4-nitroquinoline N-oxide (NQO, 3 microM) plus 0.3 mM paracetamol contained twice as many DNA SSBs compared to MNC exposed to NQO alone, and the level of SSBs decreased more slowly during repair in the presence of paracetamol. Deoxyribonucleosides reversed the effects of paracetamol. SSBs induced by MMS or X-rays (2.6 Gy) were not increased by paracetamol. Resting and growth-stimulated MNC, HL-60 cells, rat hepatocytes and human fibroblasts exposed to UV-C (3-12 J/m2) showed varying levels of transient SSBs formed during repair but these were consistently higher in the presence of paracetamol (0.3-1 mM). In rat testicular cells SSBs were induced by NQO and the levels were further increased in the presence of paracetamol, whereas after UV almost no SSBs were detected during repair. The cell-type specific levels of transient SSBs after UV did not correlate with the rate of incision of DNA lesions, measured as the rate of SSB accumulation in the presence of repair inhibitors Ara C plus hydroxyurea. Transient SSBs were present in resting MNC for at least 24 h after UV and paracetamol increased these breaks 4-fold however the overall rate of removal of excisable photodamage during repair did not appear to be reduced by the presence of paracetamol. The present data indicate that paracetamol interferes with nucleotide excision repair in several mammalian cell types. This constitutes a mechanism by which paracetamol may contribute to genotoxicity in humans.

4-Nitroquinoline-1-oxide↗
PubMed1994

[Biological pollution of indoor air].

Biological pollution of indoor air can consist of viruses, bacteria, fungi, fungal spores, mites, dander and metabolic products from the microorganisms. The occurrence of such pollution can occasionally cause building-related adverse health effects. Allergens produced by house dust mites and in the dander of furred domestic animals are generally regarded to be among the most important causes of disease episodes in atopic individuals. Bacteria and fungi as such cause building-related disease more rarely. An exception is respiratory infections caused by Legionella bacteria. Other possible health effects of biological indoor air pollution have been suggested, but the data are inconclusive.

Air Microbiology↗
PubMed1994

[DNA damages caused by paracetamol].

Studies on cells in vitro and animal experiments show that paracetamol may bind covalently to DNA, inhibit DNA-replication and DNA-repair synthesis, and cause chromosomal aberrations in somatic cells. In two studies a higher level of chromosomal aberrations was found in lymphocytes after exposure of human volunteers to therapeutic doses of paracetamol, but in a third study the results were negative. Genotoxic effects of paracetamol have been demonstrated both in vitro and in vivo at or near therapeutic concentrations. Overall, the data indicate that paracetamol-use may contribute to an increase in the total burden of DNA-damage in man. Higher risk of cancer after exposure to paracetamol has not been demonstrated in epidemiological studies, nor has increased risk of cancer been unequivocally documented from animal experiments. It is generally accepted, however, that exposure that may cause DNA-damage in man should be reduced and if possible avoided. The therapeutic benefit of using paracetamol should therefore be carefully evaluated, taking into consideration its potential for inducing acute and chronic and genotoxic effects.

Acetaminophen↗
PubMed1994

Genotoxicity of paracetamol in mice and rats.

The genotoxicity of paracetamol, including covalent binding to DNA, induction of DNA single-strand breaks (SSBs), and inhibition of replicative and repair synthesis of DNA, has been investigated in rodents in vivo. In the covalent binding studies male ICR mice were fasted and pretreated with diethyl maleate to deplete hepatic glutathione (GSH) and 300 mg/kg of [G-3H]paracetamol was administered intraperitoneally (i.p.). Animals were killed at 2, 6, 24, 72 and 168 h after paracetamol and hepatic or renal DNA and protein were isolated and the extent of covalent binding determined. Maximal binding to liver DNA, 8.4 +/- 3.1 pmol/mg of DNA, was observed at 2 h and declined rapidly to 2.6 pmol/mg at 24 h. Measurable binding (1.4 pmol/mg of DNA) was detected at 7 days. Protein binding in the liver in these animals peaked between 2 and 6 h (887 pmol/mg of protein at 2 h) and declined monoexponentially to 52 pmol/mg at 7 days. Although based on a limited body of data, covalent binding was also detected in DNA isolated from the kidney. DNA damage measured as SSBs by alkaline elution was induced in nuclear DNA isolated from the liver but not from the kidney, 2 h after i.p. injection of paracetamol at 600 mg/kg in male B6 mice. Only marginal DNA damage was noted at 300 mg/kg. The alkaline elution profile from damaged liver nuclei was markedly biphasic, suggesting that breaks were induced in DNA from a subpopulation of liver cells. The non-hepatotoxic paracetamol regioisomer, acetyl-m-aminophenol (600 mg/kg), which binds covalently to proteins, did not cause DNA SSBs.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Nitroquinoline-1-oxide↗
PubMed1993

Paracetamol inhibits UV-induced DNA repair in resting human mononuclear blood cells in vitro.

The effects of paracetamol on the repair of DNA damage in resting human peripheral mononuclear blood cells (MNC) in vitro were investigated by means of the alkaline elution technique. Low doses of UV light (254 nm, 3 J/m2) caused a transient increase in the amount of DNA single-strand breaks and alkali-labile sites (SSBs). Paracetamol (0.1-1.0 mM) present during post-irradiation incubation approximately doubled the maximum level of UV-induced (1-3 J/m2) SSBs and delayed the completion of repair. Although there were considerable variations between cells prepared from different donors, the level of UV-induced DNA SSBs was always higher with paracetamol. Hydroxyurea (0.3 mM), an inhibitor of ribonucleotide reductase, caused a similar increased accumulation and slow removal of SSBs, whereas cytosine-1-beta-D-arabinofuranoside (Ara C) (10 microM), an inhibitor of DNA polymerases, led to a steady accumulation of DNA SSBs. The increased levels of SSBs caused by paracetamol or hydroxyurea were both completely suppressed by concomitant addition of deoxyribonucleosides; this supports the notion that paracetamol as well as hydroxyurea inhibits ribonucleotide reductase. About the same rates of formation and removal of UV-induced SSBs were observed in T lymphocytes, B lymphocytes and monocytes. In both isolated T lymphocytes and B lymphocytes, paracetamol (0.3 mM) markedly increased the level of DNA SSBs induced by UV, whereas monocytes seemed to be less sensitive to the effect of paracetamol. It is concluded that the inhibition of DNA repair may contribute to the clastogenic effects of paracetamol.

Acetaminophen↗
PubMed1991

Comparative cytotoxic effects of acetaminophen (N-acetyl-p-aminophenol), a non-hepatotoxic regioisomer acetyl-m-aminophenol and their postulated reactive hydroquinone and quinone metabolites in monolayer cultures of mouse hepatocytes.

Toxic effects of acetaminophen (paracetamol, N-acetyl-p-aminophenol, APAP) in monolayer cultures of mouse hepatocytes developed over a period of 18 hr. N-Acetyl-m-aminophenol (AMAP) was approximately 10-fold less toxic than APAP, despite the fact that it bound covalently to a greater extent to hepatocyte macromolecules. AMAP did not deplete glutathione to as great an extent as APAP, indicating that their reactive metabolites may bind to different proteins or that oxidative damage in addition to arylation of proteins may be involved in the development of cell death. The toxicity of 3-methoxy-acetyl-p-aminophenol was similar to that of APAP, whereas the other hydroquinone and quinone metabolites were 8-10 times more cytotoxic than APAP. The potencies of these analogs were in the order: acetyl-m-aminophenol-p-benzoquinoneimine greater than or equal to 2,5-dihydroxyacetanilide greater than or equal to 3-methoxy-p-benzoquinone greater than or equal to N-acetyl-p-benzoquinone imine (NAPQI) greater than or equal to acetyl-m-aminophenol-o-benzoquinone greater than or equal to 3-hydroxy-acetyl-p-aminophenol. The relative toxic potencies of the hydroquinone and quinone metabolites of AMAP were comparable to that of NAPQI, and do not readily explain the marked difference between the cytotoxic effects of AMAP and APAP.

Acetaminophen↗
PubMed1991

Genotoxic effects of the drinking water mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX) in mammalian cells in vitro and in rats in vivo.

The potent bacterial mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]- furanone) (MX), which is formed during chlorination of drinking water and accounts for about one third of the Ames mutagenicity of tap water, has been studied with respect to its genotoxicity in vitro and in vivo. Treatment with 30-300 microM MX (1 h) induced DNA damage in a concentration-dependent manner in suspensions of rat hepatocytes, as measured by an automated alkaline elution system. The effect was similar in hepatocytes from PCB-induced and uninduced rats. DNA damage was induced in V79 Chinese hamster cells and in isolated rat testicular cells, at the same concentration level as in hepatocytes. Pretreating testicular cells with diethylmaleate, which depletes 85% of cellular glutathione, had no significant effect on the DNA damage induced by MX. The treatment conditions used in the alkaline elution experiments were not cytotoxic to any of the cell types used, as determined by trypan blue exclusion. V79 cells exposed to 2-5 microM MX (2 h) showed an increased frequency of sister-chromatid exchanges (SCE) whereas no significant effect on HGPRT mutation induction was observed. Higher concentrations (greater than 10 microM, 2 h) apparently blocked cell division. The data indicate that MX can react directly with DNA or that MX is metabolized to an ultimate mutagen via some enzyme which is common in mammalian cells. The in vivo experiments showed no evidence of genotoxicity after intraperitoneal (18 mg/kg, 1 h) or oral (18, 63 or 125 mg/kg, 1 h) administration of MX, as measured by alkaline elution, in any of the following organs: the pyloric part of the stomach, the duodenum, colon ascendens, liver, kidney, lung, bone marrow, urinary bladder and the testes. In conclusion, MX is a direct-acting genotoxicant in vitro but no in vivo genotoxicity was detected.

4-Nitroquinoline-1-oxide↗
PubMed1991

Increased frequency of sister-chromatid exchange and chromatid breaks in lymphocytes after treatment of human volunteers with therapeutic doses of paracetamol.

Paracetamol was given to 10 healthy human volunteers in 3 doses of 1 g each during a period of 8 h. Blood samples for lymphocyte cultures were taken before and 24 h after paracetamol administration. A small but significant increase was found in the frequency of sister-chromatid exchanges (SCE) after intake of paracetamol (0.187 +/- 0.030 per chromosome before and 0.208 +/- 0.024 per chromosome after). After exposure the mean frequency of chromatid breaks per 100 cells was significantly increased (2.16 +/- 1.33 versus 0.33 +/- 0.50 before exposure). Exposure of human lymphocytes in vitro showed that concentrations of paracetamol above 0.1 mM induced inhibition of replicative DNA synthesis. Increased SCE was found in lymphocytes exposed to 1-10 mM paracetamol for 2 h. Furthermore, 0.75-1.5 mM paracetamol exposure for 24 h increased the frequency of chromatid and chromosome breaks in the lymphocytes. The paracetamol-induced SCE and chromosome aberrations may be secondary effects of paracetamol-induced inhibition of DNA synthesis or due to covalent binding of paracetamol metabolite(s) to DNA.

Acetaminophen↗
PubMed1991

Co-culture systems for assessing the stability and genotoxicity of reactive 1,2-dibromo-3-chloropropane (DBCP) metabolites.

1,2-Dibromo-3-chloropropane (DBCP) induced DNA damage, measured by alkaline elution, at low concentrations (5-10 microM) in suspensions of hepatocytes and testicular cells isolated from rats. At higher concentrations (greater than or equal to 100 microM) DBCP caused DNA damage and increased the frequency of sister chromatid exchanges in Chinese hamster V79 cells. When DBCP (2.5-10 microM) was tested for its ability to cause unscheduled DNA synthesis (UDS) in monolayers of liver cells isolated from untreated rats, a clear positive response was obtained. No increase in UDS was detectable when liver cells isolated from PCB-pretreated rats were used. In contrast, DBCP (greater than or equal to 50 microM) was metabolized in hepatocytes from PCB-pretreated rats to products mutagenic to Salmonella typhimurium TA100 in co-culture with the hepatocytes, whereas control hepatocytes were substantially (40-fold) less active. No bacterial mutagenicity could be detected when the TA100 strain was co-incubated with isolated rat testicular cells and DBCP. In co-cultures of hepatocytes and V79 cells DBCP-induced DNA damage in V79 cells occurred at low concentrations (10 microM DBCP) compared to the concentration (100 microM) needed to induce DNA damage in the V79 cells incubated without hepatocytes. Testicular cells were not able to enhance DBCP-induced DNA damage in the V79 cells. The data indicate that the putative reactive DBCP episulphonium ion metabolite formed in the testicular cells presumably responsible for testicular cell DNA damage, is not capable of escaping the cell where it is formed. Other reactive DBCP metabolites generated in the liver cells seem to be able to interact with the DNA of neighbouring cells.

Animals↗
PubMed1990

Paracetamol inhibits replicative DNA synthesis and induces sister chromatid exchange and chromosomal aberrations by inhibition of ribonucleotide reductase.

Effects of paracetamol have been studied in a hydroxyurea (HU)-resistant mouse mammary tumour cell line TA3H2, shown to overproduce the small subunit of ribonucleotide reductase. These TA3H2 cells were much more resistant than the TA3H (wild-type) cells towards the inhibitory effect of paracetamol on cell growth, IC50 0.55 mM paracetamol for the wild-type compared to 2.7 mM for the HU-resistant cells. The reduced cell growth was due to an inhibition of replicative DNA synthesis, judged from an increased percentage of cells in S-phase measured by flow cytometry. Furthermore, in the wild-type cells, the increase in the number of cells in S phase was already observed at 0.1 mM while in the HU-resistant cell line this effect was first seen at 3.0 mM paracetamol. HU inhibits ribonucleotide reductase by destroying a tyrosyl free radical located on the small subunit of the enzyme. By electron paramagnetic resonance we demonstrate that paracetamol added to crude cell extracts of HU-resistant cells also immediately destroys this radical. These results show that paracetamol reduces DNA synthesis by a specific inhibition of ribonucleotide reductase. A concentration-dependent induction of sister chromatid exchanges was found both with paracetamol (1.0-10 mM) and HU (0.3-3 mM) in wild-type cells whereas no such increase was observed in HU-resistant cells. Paracetamol (1 mM for 2 h) also increased the number of chromosomal aberrations CAs in wild-type cells (i.e. chromatid breaks and chromatid exchanges). The frequency of CAs was not increased in HU-resistant cells at paracetamol concentrations up to 10 mM.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1989

Genotoxicity of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): formation of 2-hydroxamino-PhIP, a directly acting genotoxic metabolite.

Hepatocytes isolated from Aroclor 1254 (PCB) pretreated rats metabolized 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to a reactive metabolite that induced DNA damage measured by alkaline elution or as increased unscheduled DNA synthesis. PhIP induced mutations in Salmonella typhimurium TA98 and DNA strand breaks and sister chromatid exchange(s) in Chinese hamster V79 cells co-incubated with PCB-hepatocytes. No, or only minor genotoxic, effects were observed when hepatocytes from non-induced rats were used. The bacterial mutagenicity could be inhibited by alpha-naphthoflavone, indicating a role of P-450 in the activation of PhIP. At least eight different metabolites could be separated on HPLC after PhIP had been incubated with PCB-hepatocytes. All of the directly acting mutagenicity towards S.typhimurium TA98 co-eluted with one of the metabolites. The identity of this metabolite was concluded to be 2-hydroxamino-PhIP based on the following evidence: (i) it reduced ferric ion to ferrous ion as hydroxylamines do, (ii) it had an identical UV spectrum and chromatographic properties as a species formed upon reduction of 2-nitro-PhIP by NADPH P-450 reductase. This product displayed a major peak at m/z 241 during thermospray mass spectrometry in the positive-ion mode as would be expected from 2-hydroxamino-PhIP. 2-Hydroxamino-PhIP was directly genotoxic both to TA98 and V79 cells. The genotoxic activity of the medium after removing the hepatocytes remained stable for several hours. Compared to 2-amino-3,4-dimethylimidazo[4,5-f]quinolone (MeIQ), PhIP caused a much larger increase in DNA damage in V79 cells (with hepatocyte activation), whereas MeIQ was more potent with respect to DNA damage induced in hepatocytes and bacteria.

Animals↗
PubMed1989

Comparative genotoxicities of procarbazine and two deuterated analogs in mammalian cells in vitro and in vivo.

N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine; 50-1000 micrograms/ml) induced DNA damage in hepatocytes measured by an automated alkaline elution method, whereas no significant increase in unscheduled DNA synthesis was seen. In hepatocytes isolated from PCB-treated rats, DNA damage was detected in both test systems at concentrations as low as 1-10 micrograms/ml. DNA damage, as measured by alkaline elution and sister-chromatid exchange(s), was observed also in V79 cells incubated with PCB-hepatocytes. In contrast, no mutagenic activity was observed in the Salmonella typhimurium strain TA1530 co-incubated with the hepatocytes. Exposure of rats to low doses of procarbazine (25-50 mg/kg) caused DNA damage measured by alkaline elution in liver and testis, with the liver being somewhat more sensitive. The genotoxicity caused by procarbazine was increased by a factor of 2-3 in both organs by PCB-treatment of the rats. N-isopropyl-alpha-(2-methyl-hydrazino)-p-[alpha,alpha-2H2]toluamide (d2-procarbazine), was found to cause significantly less genotoxicity in control rats than either procarbazine itself, or N-isopropyl-alpha-(2-[alpha,alpha,alpha-2H3]methylhydrazino)-p-tol uamide (d3-procarbazine). This indicates that benzylic C-H oxidation of procarbazine is an important step in the activation of procarbazine to genotoxic metabolites in uninduced rats.

Animals↗