Different Change Patterns of the Isozymes of Cytochrome P450 and Glutathione S-Transferases in Chemically Induced Liver Damage in Rat.

Wang, Rui-Sheng; Nakajima, Takahito; Honma, Takeshi

doi:10.2486/indhealth.37.440

Cited by 18 publications

(10 citation statements)

References 30 publications

(1 reference statement)

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“…Furthermore, it is well characterized that sustained ROS challenge aggravated cell viability when the activity of CYP2E1 was increased by chemical inducers or enzyme overexpression [54]. In an effort to find the link of hepatocyte death to CYP2E1-dependent metabolism, we measured CYP2E1 protein and mRNA levels after DMF and/or CCl 4 treatment; DMF treatment at the daily dose of 500 mg/kg for 3 days increased the expression of the CYP2E1 level (~1.5-fold), which is consistent with the report that DMF induced CYP2E1 expression [55,56]. CCl 4 is known to reduce CYP2E1 levels by producing reactive metabolites and the consequent suicide substrate inhibition [57].…”

Section: Potential Mechanism Of Dmf-induced Liver Toxicitysupporting

confidence: 85%

Clinical Outcomes of Occupational Exposure to N,N-Dimethylformamide: Perspectives from Experimental Toxicology

Kim

2011

Safety and Health at Work

109

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N,N-Dimethylformamide (DMF) is globally used as an organic solvent in the production of synthetic leather and resins because of its low volatility, making it an attractive industrial material. Despite its excellent property as a chemical solvent, utilization of DMF is somewhat controversial nowadays due to its hazardous effects on exposed workers in work places. Many toxification cases are being reported globally and the number of cases of liver damage is still increasing in developing countries. On account of this, a series of epidemiologic surveys are being conducted to understand the degrees of liver damage caused by DMF exposure. Furthermore, many investigations have been performed to clarify the mechanism of DMF-induced liver toxicity using both human and experimental animal models. This review summarizes the current occupational cases reported on liver damage from workers exposed to DMF in industrial work places and the research results that account for DMF-induced liver failure and possible carcinogenesis. The findings reviewed here show the synergistic toxicity of DMF exposure with other toxicants, which might occur through complicated but distinct mechanisms, which may extend our knowledge for establishing risk assessments of DMF exposure in industrial work places.

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Section: Potential Mechanism Of Dmf-induced Liver Toxicitysupporting

confidence: 85%

Clinical Outcomes of Occupational Exposure to N,N-Dimethylformamide: Perspectives from Experimental Toxicology

Kim

2011

Safety and Health at Work

109

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“…Of note, nephrotoxicant induced‐heightened expression of Spp1 in kidney has been reported by others (Wang et al ., 2008). Gstp1, an important member of the glutathione family involved in drug metabolism (Wang et al ., 1999), has also been previously implicated (clinically) in renal disease (Agrawal et al ., 2007). Cluster analyses also led to the identification of changes in gene expression of Cyp3a1 in liver as a possible ‘fingerprint’ of drug‐induced hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and genotypic assessment of concomitant drug‐induced toxic effects in liver, kidney and blood

Dadarkar

Fonseca

Mishra

et al. 2011

J of Applied Toxicology

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Several studies have characterized drug-induced toxicity in liver and kidney. However, the majority of these studies have been performed with 'individual' organs in isolation. Separately, little is known about the role of whole blood as a surrogate tissue in drug-induced toxicity. Accordingly, we investigated the 'concurrent' response of liver, kidney and whole blood during a toxic assault. Rats were acutely treated with therapeutics (acetaminophen, rosiglitazone, fluconazole, isoniazid, cyclophosphamide, amphotericin B, gentamicin and cisplatin) reported for their liver and/or kidney toxicity. Changes in clinical chemistry parameters (e.g. AST, urea) and/or observed microscopic tissue damage confirmed induced hepatotoxicity and/or nephrotoxicity by all drugs. Drug-induced toxicity was not confined to an 'individual' organ. Not all drugs elicited significant alterations in phenotypic parameters of toxicity (e.g. ALT, creatinine). Accordingly, the transcriptional profile of the organs was studied using a toxicity panel of 30 genes derived from literature. Each of the test drugs generated specific gene expression patterns which were unique for all three organs. Hierarchical cluster analyses of purported hepatotoxicants and nephrotoxicants each led to characteristic 'fingerprints' (e.g. decrease in Cyp3a1 indicative of hepatotoxicity; increase in Spp1 and decrease in Gstp1 indicative of nephrotoxicity). In whole blood cells, a set of genes was derived which closely correlated with individual drug-induced concomitant changes in liver or kidney. Collectively, these data demonstrate drug-induced multi-organ toxicity. Furthermore, our findings underscore the importance of transcriptional profiling during inadequate phenotypic anchorage and suggest that whole blood may be judiciously used as a surrogate for drug-induced extra-hematological organ toxicity.

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“…33 No. 3 ously reported experimental studies that repeated inhalation exposure to and oral administration of DMF for up to 13 weeks induce centrilobular hypertrophy and necrosis of hepatocytes and increased cytolytic release of ALT and aspartate transaminase (AST) into plasma (Lundberg et al, 1981;Craig et al, 1984;Kennedy Jr. et al, 1986;Wang et al, 1999;Chieli et al, 1995;Lynch et al, 2003, Senoh et al, 2003. In addition, some of these studies demonstrated that a proliferative lesion including to DMF (Lynch et al, 2003;Senoh et al, 2003).…”

Section: Note2mentioning

confidence: 99%

“…Medical case reports, epidemiological studies and experimental toxicology studies on health or toxic effects of DMF revealed that DMF primarily affects the liver in humans Wang et al, 1991;Redlich et al, 1990;Fiorito et al, 1997;Nomiyama et al, 2001) and in experimental animals (Lundberg et al, 1981;Craig et al, 1984;Kennedy Jr. et al, 1986;Wang et al, 1999;Chieli et al, 1995;Lynch et al, 2003;Senoh et al, 2003;Malley et al, 1994;Senoh et al, 2004). The International Agency for Research on Cancer (IARC, 1999) made an carcinogenicity to humans (Group 3).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, it has been recognized that 13-week inhalation exposure of rats and mice to DMF vapor induces such related lesions as necrosis, fragmented or enlarged nuclei and increased mitotic et al, 2003;Senoh et al, 2003). It is important to understand whether exposure of a general population to low levels of ubiquitously present DMF through both inhalation and ingestion may cause any subtle but untoward outcome on the liver, since the toxic effects have been evidenced in the experimental animals exposed to far high levels of DMF through single-route exposure of either inhalation or ingestion (Lundberg et al, 1981;Craig et al, 1984;Kennedy Jr. et al, 1986;Wang et al, 1999;Chieli et al, 1995;Lynch et al, 2003;Senoh et al, 2003;Malley et al, 1994;Senoh et al, 2004). Thus the present study was designed to examine hepatotoxicity induced by combined inhalation and oral exposures of male rats to DMF in comparison with those by single-route exposure through either inhalation or ingestion.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced proliferative response of hepatocytes to combined inhalation and oral exposures to N,N-dimethylformamide in male rats

et al. 2008

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Male Wistar rats were exposed by inhalation to N,N-dimethylformamide (DMF) at 0 (control), 200 or 400 ppm (v/v) for 6 hr/day, 5 days/week and 4 weeks, and each inhalation group received DMF-formulated drinking water at 0, 800, 1,600 or 3,200 ppm (w/w) for 24 hr/day, 7 days/week and 4 weeks. Both the combined inhalation and oral exposures and the single-route exposure through inhalation or ingestion induced centrilobular hypertrophy and single-cell necrosis of hepatocytes, increased plasma levels of alanine aminotransferase (ALT), increased percentage of proliferating cell nuclear antigen (PCNA)-positive hepatocytes without glutathione-S-transferase placental form (GST-P)-positive liver foci, and increased relative liver weight. Those hepatic parameters of the DMF-induced effects were classified into hypertrophic, necrotic and proliferative responses according to the pathological characteristics of affected liver. While magnitudes of the hypertrophic and necrotic responses were linearly increased with an increase in amounts of DMF uptake in the single-route exposure groups, those dose-response relationships tended to level off in the combined-exposure groups. Saturation of the hypertrophic and necrotic responses at high dose levels might be attributed to suppression of the metabolic conversion of DMF to its toxic metabolites. Percentage of PCNA-stained hepatocytes classified as the proliferative response was increased more steeply in the combined-exposure groups than in the single-route exposure groups. It was suggested that the proliferative response of hepatocytes to the combined exposures would be greater than that which would be expected under an assumption of additivity for the component proliferative responses to the single-route exposures through inhalation and ingestion.

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Different Change Patterns of the Isozymes of Cytochrome P450 and Glutathione S-Transferases in Chemically Induced Liver Damage in Rat.

Cited by 18 publications

References 30 publications

Clinical Outcomes of Occupational Exposure to N,N-Dimethylformamide: Perspectives from Experimental Toxicology

Clinical Outcomes of Occupational Exposure to N,N-Dimethylformamide: Perspectives from Experimental Toxicology

Phenotypic and genotypic assessment of concomitant drug‐induced toxic effects in liver, kidney and blood

Enhanced proliferative response of hepatocytes to combined inhalation and oral exposures to N,N-dimethylformamide in male rats

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