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PubMed1996

The effect of malotilate on type III and type IV collagen, laminin and fibronectin metabolism in dimethylnitrosamine-induced liver fibrosis in the rat.

BACKGROUND/AIMS: Dimethylnitrosamine-induced liver damage was used as an experimental model to study the effect of malotilate on liver fibrosis. METHODS: Deposition of type III and IV collagens, laminin and fibronectin were studied from liver section by immunohistochemical techniques using specific antibodies. Serum concentrations of aminoterminal propeptide of type III procollagen, and aminoterminal and carboxyterminal domains of type IV collagen were determined by radioimmunoassays from both malotilate-treated and untreated animals with dimethylnitrosamine injury. RESULTS: A significant elevation of all three serum parameters was observed after 3 weeks of hepatic injury in animals without malotilate treatment, and a constant increase was noted in the amounts of hepatic type III and IV collagens, laminin and fibronectin. Malotilate prevented increases in serum markers of type III and IV collagen synthesis as well as accumulation of the collagens, laminin and fibronectin in the liver. CONCLUSIONS: The results suggest that serum marker determinations can be used to monitor changes in type III and IV collagen synthesis in the liver. The data indicate that malotilate has a preventive effect in dimethylnitrosamine-induced experimental hepatic fibrosis.

Animals↗
PubMed1997

Heterogeneity of the "oval-cell" response in the hamster liver during cholangiocarcinogenesis following Clonorchis sinensis infection and dimethylnitrosamine treatment.

BACKGROUND: Small intraportal "oval" cells which appear in the livers of humans and experimental animals after liver injury, are suspected to be early progenitor cells for both hepatocytes and bile duct cells, as well as cells of origin of hepatocellular and cholangiocellular carcinomas. METHODS: The origin and fate of small "oval" cells expressing different immunohistologic phenotypes and ultrastructural appearance were examined in livers of Syrian hamsters during cholangiocarcinogenesis induced by dimethylnitrosamine and promoted by Clonorchis sinensis infection. RESULTS: Three different "oval" cell types are identified in portal and/or periportal areas: 1) Small periductal cells with abundant heterochromatin and scant cytoplasm that are negative for AFP, CK19, OV-6 and GST-p (primitive oval cells); 2) Glycogen-rich cells, positive for AFP, but negative for CK19, OV-6 and GST-p mainly adjacent to ductal plates (hepatocyte-like oval cells); and 3) small cells with desmosomes and basement membrane, containing GST-p CK19 and OV-6 but negative for AFP, present in ducts (ductular-like oval cells). It appears that C. sinensis infection stimulates proliferation and differentiation of small ductular or periductal cells (primitive oval cells) into either hepatocyte-like oval cells, which mature into hepatocytes without malignant transformation, or into ductular-like oval cells. CONCLUSIONS: We propose that the ductular-like oval cells are precursors of dysplastic ductular cells that give rise to cholangiocarcinomas after dimethylnitrosamine treatment and conclude that primitive oval cells are bipolar progenitor cells for hepatocytes and biliary cells, and that activation (initiation) of these cells by carcinogen (dimethylnitrosamine), followed by stimulation of proliferation of biliary cells by C. sinensis, promotes primitive oval cells or their progeny (ductular-like oval cells) to transform into cholangiocarcinomas.

Animals↗
PubMed1998

Retinyl palmitate reduces hepatic fibrosis in rats induced by dimethylnitrosamine or pig serum.

BACKGROUND/AIMS: Lipid peroxidation has been found to be associated with Ito cell activation. Ito cells are the principal collagen-producing cells and the main storage sites of retinoids. However, the relationship between retinoids and hepatic fibrosis is complex. The aim of this study was to elucidate the role of retinoids as a fibrosuppressant: the effects of retinoids on hepatic fibrosis induced in rats by dimethylnitrosamine or pig serum, as well as on rat Ito cells in primary culture, were examined in order to assess the antioxidant activity of retinoids. METHODS: Male Wistar rats were given a single injection of 40 mg/kg dimethylnitrosamine or 0.5 ml PS twice weekly for 10 weeks. In each model, rats were treated with retinyl palmitate for 2 weeks before hepatotoxin treatments or for the last 2 weeks of the treatments. The cumulative amount of retinyl palmitate administered in each experiment was 2, 10, or 20x10(4) IU/rat. RESULTS: Retinyl palmitate treatment before or after administration of dimethylnitrosamine or pig serum suppressed the induction of hepatic fibrosis, restored hepatic retinyl palmitate levels, prevented increases in hepatic levels of collagen and malondialdehyde, a product of lipid peroxidation, and prevented increases in deposition of type III collagen and the number of alpha-smooth muscle actin (alpha-SMA) positive-Ito cells in the liver. Retinyl palmitate supplementation resulted in a dose-dependent reduction of alpha-SMA expression and an oxidative burst in cultured Ito cells. In addition, retinyl palmitate inhibited Fe2+/adenosine 5'-diphosphate-induced lipid peroxidation in rat liver mitochondria and showed radical scavenging activity. CONCLUSIONS: These findings suggest that retinyl palmitate may suppress the induction of hepatic fibrosis, at least in part, by the inhibition of Ito cell activation through its antioxidant activity.

Animals↗
PubMed1965

REACTION OF THE CARCINOGEN DIMETHYLNITROSAMINE WITH PROTEINS AND WITH THIOL COMPOUNDS IN THE INTACT ANIMAL.

1. [(14)C]Dimethylnitrosamine was administered to rats, and the formation of free and protein-bound S-methylcysteine was investigated. 2. Very little S-methylcysteine was found in liver acid-soluble fraction, in liver protein or in urine. 3. The methylhistidines formed in liver protein were found to have largely disappeared by 6 days after injection of dimethylnitrosamine. 4. The significance of these results in the carcinogenic action of dimethylnitrosamine is discussed.

Alkylation↗
PubMed1976

Methylated purines in the deoxyribonucleic acid of various Syrian-golden-hamster tissues after administration of a hepatocarcinogenic dose of dimethylnitrosamine.

1. DNA was extracted from livers, kidneys and lungs of Syrian golden hamsters at various times (up to 96h) after injection of a hepatocarcinogenic dose of [14C]dimethylnitrosamine. Purine bases were released from the DNA by mild acid hydrolysis and separated by Sephadex G-10 chromatography. 2. At 7h after dimethylnitrosamine administration liver DNA was alkylated to the greatest extent, followed by that of lung and kidney, the values for which were 8 and 3% respectively of those for liver. 3. The O6-methylguanine/7-methylguanine ratios were initially the same in all three organs and in the liver DNA of rats under similar conditions of dose. 4. O6-Methylguanine was the most persistent alkylated purine in all three hamster tissues. There was evidence for excision of 7-methyl-guanine, the highest activity for this being present in the liver. 5. Detectable amounts of the minor products 3-methyladenine, 1-methyladenine, 3-methylguanine and 7-methyladenine were present in most hamster tissues, and their individual rates of loss from liver DNA were determined. 6. Ring-labelling of the normal purines in DNA was highest in the liver, followed closely by the lung (80% of that in liver) whereas the kidney had very low incorporation (3% of that in liver). 7. The results are discussed with respect to the hepatotoxicity of dimethylnitrosamine, the miscoding potential of the various alkylation products and the induction of liver tumours in hamsters.

Adenine↗
PubMed1981

Early effects of dimethylnitrosamine on the initiation of protein synthesis in mouse liver.

1. Dimethylnitrosamine (37.5 mg/kg body wt.) was administered to mice by a single intraperitoneal injection, and the early effects on protein synthesis and related functions were studied in a liver S-30 system. 2. The incorporation of [14C]leucine into protein decreased rapidly after dimethylnitrosamine administration. The effect was associated with a decreased ability of the system to utilize methionyl-tRNAfMet and formyl-methionyl-tRNAfMet for 80 S ribosomal initiation-complex formation (primary initiation), and a loss of poly(A)-containing RNA from the postmicrosomal fraction. All the three effects developed simultaneously, and were clearly demonstrable within 15 min. 3. Initiation-complex formation in the polyribosomal fraction (re-initiation) was decreased to the same extent as the primary initiation, indicating that the initiation defect was not a result of the decrease in free mRNA. 4. The inhibition of initiation was only manifest at the joining of the 40 S pre-initiation complex to 60 S ribosomal subunits. It was not a result of methionyl-tRNAfMet deacylation. The functions between the formation of the methionyl-tRNAfMet-containing 80 S ribosomal complex and the first translocation on the ribosome were not involved, since the incorporation of formylmethionine into N-terminal polypeptides decreased to the same extent as the 80 S initiation-complex formation. 5. Inhibitors of protein synthesis (cycloheximide and pactamycin) decreased poly(A)-containing RNA in the postmicrosomal fraction in a similar way to dimethylnitrosamine.

Animals↗
PubMed1981

Non-involvement of nucleolytic activities in the early effect of dimethylnitrosamine on the content of free mRNA in mouse liver.

1. After dimethylnitrosamine (DMNA) administration to mice, the content of poly(A)-containing RNA decreases rapidly in the postmicrosomal fraction of the liver. We report here that the loss of free mRNA is not a result of increased nucleolytic activity. On the contrary, a decreased activity of microsomal endonuclease, assayed by its effect on polyribosomal mRNA, was demonstrated already 15 min after the administration of DMNA at 37.5 mg/kg body wt. The loss of activity was more pronounced in the rough than in the smooth membranes. Total detergent-released microsomal nucleases, as assayed by use of labelled poly(U) as substrate, showed a less rapid decline. No corresponding increase in enzyme activities was observed in the postmicrosomal fraction. 2. The dimethylnitrosamine effect on the microsomal endonuclease was not accounted for by altered lysosomal contamination of the microsomal fraction. 3. No early effect of dimethylnitrosamine administration was found on the cytoplasmic ribonuclease inhibitor.

Animals↗
PubMed1987

Methylation of DNA guanine during the course of induction of liver cancer in hamsters by hydrazine or dimethylnitrosamine.

Hydrazine is carcinogenic to the mouse and rat, but three earlier studies have reported no carcinogenicity of hydrazine in the hamster. Administration of hydrazine to mice, rats and hamsters results in rapid methylation of liver DNA guanine for which endogenous formaldehyde appears to be the source of the methyl moiety. Hamsters were given hydrazine sulfate at 170, 340 and 510 mg/l in the drinking water for 2 years [average dose of 4.6, 8.3 and 10.3 mg hydrazine (free base)/kg body wt over the 2-year period], during which levels of methylation of DNA guanine in liver, kidney and lung, and histopathologic examinations of these tissues were carried out; dimethylnitrosamine, as a positive control, was administered at 10 mg/l in the drinking water (average dose of 1.1 mg/kg body wt over the 4-month measurement period). Both 7-methylguanine and O6-methylguanine were readily detectable at 6 months exposure in hamsters given hydrazine or dimethylnitrosamine; in hydrazine-treated animals only trace amounts of these bases could be detected after 12 months exposure; these bases were again detected in liver DNA at exposure times of 18 and 24 months. Hepatocellular carcinomas were observed in hamsters treated at the highest dose of hydrazine sulfate after 78 weeks of exposure; the incidence of liver cancer was dose-related over the course of the experiment: 32% for hamsters exposed to 510 mg hydrazine sulfate/l, 12% for 340 mg/l and none at 170 mg/l. Hamsters given dimethylnitrosamine developed high levels of 7-methylguanine and even higher levels of O6-methylguanine and both liver cholangiocellular carcinomas (73% incidence), as reported before, and hepatocellular carcinomas (27% incidence), a new finding. These results demonstrate for the first time that hydrazine is a liver carcinogen in the hamster and provide new information regarding the accumulation of DNA damage during the entire induction period for the carcinomas.

Animals↗
PubMed1988

Glucagon and insulin for the treatment of hepatic failure in dimethylnitrosamine-intoxicated rats.

When rats received dimethylnitrosamine every 24 h until death, plus hormone treatment after the first 24 h, the survival was enhanced between 100 and 140 h compared with the control rats, with attenuated derangements of prothrombin time and serum albumin levels at 120 h. In rats given a single dose of dimethylnitrosamine, hepatic DNA synthesis peaked at 48 h. The synthesis was increased after hormone treatment when started immediately, but not when delayed for 24 h. Hormone treatment for 3 days starting 24 h after a single dose of dimethylnitrosamine produced a rapid normalization of decreased hepatic protein content on day 9, although hepatic DNA content was not affected. These results suggest that this treatment is effective for hepatic failure, and the promotion of restoration of liver function is a contributing factor to its effect, in addition to the stimulation of hepatocyte proliferation.

Animals↗
PubMed1999

OK-432 treatment increases matrix metalloproteinase-9 production and improves dimethylnitrosamine-induced liver cirrhosis in rats.

Kupffer cells are major matrix metalloproteinase-producing cells in the liver. The production of metalloproteinases in Kupffer cells may contribute to the improvement of liver fibrosis inducing liver cirrhosis. In this study, we examined the effect of the OK-432 (a biological response modifier) on the dimethylnitrosamine-induced liver cirrhosis in rats. Dimethylnitrosamine (10 microg/ml) was injected intraperitoneally into 20 male Wistar rats 3x/week for 4 weeks. For the subsequent 4 weeks, the animals were injected with saline (1 ml, 1x/week) (Group I, n=10) or OK-432 (1 Klinishe Einheit, 1x/week) (Group II, n=10). The control rats were injected with 1 ml saline for the initial 4 weeks and subsequent 4 weeks (Group III, n=10). The degree of hepatic fibrosis, the immunolocalization of type IV collagen, hyaluronic acid, and alpha-smooth muscle actin, and the mRNA expression by Northern blotting and the activity by gelatin zymography of metalloproteinase-9 were evaluated. Serum aminotransferase, hyaluronic acid, interleukin-1beta and tumor necrosis factor-alpha levels were measured. The deposition of á-smooth muscle actin and extracellular matrix containing type IV collagen and hyaluronic acid was markedly suppressed by OK-432. The mRNA expression and the activity of metalloproteinase-9 were markedly increased by OK-432. The serum aminotransferase and hyaluronic acid levels were decreased by OK-432. The serum interleukin-1 and tumor necrosis factor-alpha values were lower than the detectable limit in all samples from all three groups. These results indicate that OK-432 increased the production of metalloproteinase-9 and improved the rat dimethylnitrosamine-induced liver cirrhosis. OK-432 is suggested to be useful for the treatment of liver cirrhosis.

Actins↗
PubMed2000

Metallothionein induced by cadmium or zinc inhibits lipid peroxidation in rats exposed to dimethylnitrosamine.

Dimethylnitrosamine (N-nitrosodimethyamine) is a potent inducer of microsomal lipid peroxidation in the liver and kidneys. The results of this study show that prior exposure of adult rats to cadmium or zinc antagonises the effect of dimethylnitrosamine on lipid peroxidation by inducing increased metallothionein synthesis. Increased concentration of reduced glutathione (GSH) in the liver and kidney of rats pre-treated with cadmium or zinc and exposed to dimethylnitrosamine suggests that metallothionein inhibits oxidative stress. The presented results have been corroborated by findings that exposure of adult rats to cadmium or zinc may activate genes for metallothionein and glutathione-S-transferase, the protective proteins against oxidative stress.

Animals↗
PubMed1976

Electron microscopic observations on the morphogenesis of renal cell carcinoma induced in rat kidney by dimethylnitrosamine and N-(3,5-dichlorophenyl)succinimide.

Renal cell carcinoma was induced in rats by p.o. administration of dimethylnitrosamine, 500 ppm daily, followed by N-(3,5-dichlorophenyl) succinimide (NDPS), 5000 ppm daily. Fine structural changes of the proximal convoluted tubule cells were observed by sequential examinations of the kidney cortices at 3, 5, 12, and 24 weeks after drug administration. Early prominent structural changes of the cells induced by dimethylnitrosamine alone were the appearance of microspherules in nucleoli and of numerous lamellar bodies on the membrane structure of the cells. With the addition of NDPS, the cells exhibited edematous cytoplasm that, in contrast to the relatively intact nuclear structure, contained numerous bodies small vesicles and dark mitochondria, with markedly disarranged microvilli. After prolonged treatment with these drugs, some of the cells showed regenerating features, while others became necrotic. In the former case, large clear nuclei appeared with enlarged nucleoli containing a large amount of granular components. Ribosomes in the cytoplasm also increased in number in accordance with nucleolar changes, and edema in cytoplasm and microvilli markedly decreased. However, a considerable number of vesicles still remained in some cells. Mitochondria decreased in number and showed pleomorphism and relatively high electron density. At 24 weeks, when clear cell carcinoma was induced, the cells in the cancer tissue exhibited a variety of features in their nuclei and cytoplasm. Some cells showed intact nuclear structure and dark cytoplasm containing a large number of vesicles; others had large round clear nuclei with enlarged nucleoli and clear cytoplasm containing no vesicles. Among these cells were mixed populations of large clear cells, showing a structure similar to the cells at 12 weeks, 2.e., to nodular hyperplastic cells. The starting point of malignant transformation seemed to be 1 week after treatment with NDPS (i.e., cells at 5 weeks) and, or the precancerous stage, at 12 weeks. These results suggest that the proximal convoluted tubule cells previously damaged by dimethylnitrosamine treatment were marked for mutation and were transformed to cancer cells by additional treatment with NDPS in such a way as to disturb the permeability of the membrane system of the cell and to condense chromatin fibers.

Adenocarcinoma↗
PubMed1992

Ca(++)-activated DNA fragmentation and dimethylnitrosamine-induced hepatic necrosis: effects of Ca(++)-endonuclease and poly(ADP-ribose) polymerase inhibitors in mice.

Several hepatotoxic agents damage Ca++ regulation and produce toxic cell death in a manner consistent with a cause-and-effect relationship; however, vital targets of Ca++ remain unidentified. Recent results show that DNA may be the chief Ca++ target during apoptosis, a form of cell death considered distinct from toxic cell death or necrosis. The present studies explored whether nuclear Ca++ regulation is lost before dimethylnitrosamine-induced necrosis, whether DNA is attacked by Ca(++)-dependent endonucleases and whether inhibitors of Ca(++)-endonuclease activity and the DNA repair enzyme poly(ADP-ribose)polymerase affect necrosis. Adult male ICR mice received 100 mg/kg of dimethylnitrosamine i.p. By 2 to 4 hr, total nuclear Ca++ reached 150 to 180% of control and DNA fragmentation was 140 to 170% of control. Electrophoresis of DNA revealed a sharp decline in genomic DNA with the appearance of DNA fragments in a ladder-like pattern. Ca++ elevation and DNA fragmentation preceded toxic cell death by 4 hr or more and reached peak values at 18 to 24 hr, coincident with maximal alanine aminotransferase leakage. Aurintricarboxylic acid, a Ca(++)-endonuclease inhibitor, reduced toxicity 67%. 3-Aminobenzamide, nicotinamide adenine dinucleotide and theophylline, inhibitors of poly(ADP-ribose)polymerase-mediated DNA repair, potentiated liver damage 2-fold. These results support the hypothesis that DNA fragmentation plays a contributing role in toxic cell death induced by dimethylnitrosamine. Furthermore, the findings suggest that new opportunities may exist to moderate the toxicity of alkylating hepatotoxins by altering DNA regulation.

Animals↗
PubMed1990

Mutagenesis of mouse intestine in vivo using the Dlb-1 specific locus test: studies with 1,2-dimethylhydrazine, dimethylnitrosamine, and the dietary mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline.

The ability of three model carcinogens, 1,2-dimethylhydrazine, dimethylnitrosamine, and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, to induce mutation in a novel in vivo assay in mouse intestine has been examined. The assay is based on mutations at the Dlb-1 locus which determines the tissue specific pattern of expressio of the binding site for the lectin Dolichos biflorus agglutinin. In C57BL/6J x SWR F1 mice Dlb-1 mutants are recognized as clones of epithelial cells not staining with a peroxidase conjugate of D. biflorus agglutinin. Chronic administration of 1,2-dimethylhydrazine (20 mg/kg/week s.c. for 10 weeks) induced Dlb-1 mutants, whereas administration of a single dose did not. Similarly, chronic dimethylnitrosamine treatment p.o. (0.001% in drinking water for 8 weeks) induced Dlb-1 mutants, but acute administration did not. In contrast, neither chronic nor acute treatment of the mice with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline induced Dlb-1 mutations. The activities of 1,2-dimethylhydrazine, dimethylnitrosamine, and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in the Dlb-1 assay more accurately reflect their carcinogenic potential than do many in vitro bioassays.

1,2-Dimethylhydrazine↗
PubMed1989

Preventive effect of malotilate on dimethylnitrosamine-induced liver fibrosis in the rat.

Dimethylnitrosamine-induced liver damage, which leads to hepatic failure and death of the animal, was prevented by treatment with malotilate. The accumulation of collagen and the morphologic changes caused by dimethylnitrosamine, such as inflammatory cell accumulation and fibrosis, were also prevented by this drug. Malotilate drastically reduced the increases in the amount of type I procollagen alpha 2-chain mRNA and activities of the enzymes prolyl 4-hydroxylase and galactosylhydroxylysyl glucosyltransferase, which are early events in liver fibrosis preceding the deposition of collagen. Even when started 14 days after dimethylnitrosamine induction, malotilate treatment was able to reduce liver damage. We suggest that the effect of malotilate is a result of the inhibition of inflammation.

Animals↗
PubMed1979

Evidence for several demethylase enzymes in the oxidation of dimethylnitrosamine and phenylmethylnitrosamine by rat liver fractions.

The steady state kinetics and isotope effects were examined for demethylation of dimethylnitrosamine and phenylmethylnitrosamine, as well as their deuterated analogs, using the S-9 fraction, the microsomal pellet, and postmicrosomal supernatant from rat livers. The isotope effect (ratio of maximal rates for the deuterated and light substrates) using the S-9 from Long-Evans rat livers was found to be 1.82 for dimethylnitrosamine and 5.38 for phenylmethylnitrosamine. Phenobarbital was shown to induce dimethylnitrosamine demethylase activity in the microsomal pellet of both Long-Evans and Sprague-Dawley rats but to repress this activity in the postmicrosomal supernatant in the Long-Evans rats, while markedly increasing it in the Sprague-Dawley rats. It was also found that there was nitrosamine demethylase activity in the so-called "pH 5 enzymes" and in the supernatant from that preparation. The latter activity shows substantially different characteristics from that found in the other fractions.

Animals↗
PubMed1984

Effects of dimethylnitrosamine on RNA synthesis and metabolism in mouse liver.

Following i.p. injection of dimethylnitrosamine into male C57BL mice, synthesis of liver nuclear heterogeneous RNA was inhibited significantly, reaching approximately 20% of control within 2 hr of a dose of 40 mg/kg. Synthesis of nucleolar RNA was also inhibited, although to a smaller extent, reaching about 70% of control after the same treatment. These effects were observed both during RNA synthesis in vivo and during in vitro transcription with isolated nuclei and nucleoli. Examination of RNA polymerases I and II, isolated and partially purified by diethylaminoethyl Sephadex column chromatography, did not indicate any change either in their activities in the transcription of exogenous DNA or in their in vivo binding to chromatin. On the other hand, the activity of purified chromatin as a template for transcription by added, partially purified RNA polymerase II was significantly reduced, suggesting that carcinogen-induced damage to chromatin was the cause of the observed inhibition of heterogeneous RNA synthesis. When purified DNA was used in place of chromatin as a template for transcription by partially purified RNA polymerase II, no inhibition was observed. Dimethylnitrosamine treatment had a pronounced effect on the kinetics of appearance of the cytoplasmic RNA species. Four hr after a 40-mg/kg dose of dimethylnitrosamine, the rate of appearance in the cytoplasm of polyadenylate-containing RNA was inhibited by 50%, while that of 4S, 18S, and 28S ribosomal RNA was inhibited by over 80%.

Animals↗
PubMed1983

Effect of copper and cadmium pretreatments on DNA synthesis and thymidine kinase activity in the liver of dimethylnitrosamine-treated and partially hepatectomized rats.

Dose-related suppression of the 3H-thymidine incorporation into liver DNA of rats after a single injection of dimethylnitrosamine by copper pretreatment was observed. The 3H-thymidine incorporation was not decreased by cadmium pretreatment. On the other hand, the 3H-thymidine incorporation into liver DNA of partially hepatectomized rats was decreased by both copper and cadmium pretreatments. Thymidine kinase activity in the liver of rats treated with dimethylnitrosamine was also decreased by copper pretreatment, but the enzyme activity was not decreased by cadmium pretreatment. Copper accumulation in the liver of copper-administered rats was predominantly in the nuclear fraction, followed by the soluble fraction. Cadmium accumulation in the liver of cadmium-administered rats was predominantly in the soluble fraction, followed by the nuclear fraction. Copper accumulation in the nuclear fraction may suppress the induction of thymidine kinase in the liver of rats by dimethylnitrosamine.

Animals↗