• Toxicological Research
• /
• v.23 no.3
• /
• pp.189-196
• /
• 2007

Cytochrome P450 (P450) enzymes are the major catalysts involved in the biotransformation of various drugs, pollutants, carcinogens, and many endogenous compounds. Most of chemical carcinogens are not active by themselves but they require metabolic activation. P450 isozymes playa pivotal role in the metabolic activation. The activation of arylamines and heterocyclic arylamines (HAAs) involves critical N-hydroxylation, usually by P450. CYP1A2 plays an important role in these reactions. Broad exposure to many of these compounds might cause carcinogenicity in animals and humans. On the other hand, P450s can be also involved in the bioactivation of other chemicals including alcohols, aflatoxin B1, acetaminophen, and trichloroethylene, both in humans and in experimental animals. Understanding the P450 metabolic activation of many chemicals is necessary to develop rational strategies for prevention of their toxicities in human health. An important part is the issues of extrapolation between species in predicting risks and variation of P450 enzyme activities in humans.

• Proceedings of the PSK Conference
• /
• 2002.10a
• /
• pp.201-205
• /
• 2002

It is generally accepted that the immune system is one of the major target organs for many toxic chemicals. In addition, many toxic chemicals require metabolic activation by cytochrome P450s for their toxicity. Although the immune cells possess a limited amount of drug metabolizing capacity, metabolic activation of certain toxicants in liver and immune organs may have a significant role in immunosuppression. In the present studies, the possible role of metabolic activation by cytochrome P450s in chemical-induced immunosuppression was reviewed, with a particular emphasis on the methodological techniques to detect immunotoxicants requiring metabolic activation in vivo and in vitro. (omitted)

• Toxicological Research
• /
• v.21 no.1
• /
• pp.57-62
• /
• 2005

To investigate the mutant induction of wild ginseng culture extract, we performed chromosomal aberration assay with chinese hamster lung cell in vitro. The test concentration of the extract was decided for the standard with the 50% suppression of cell propagation in the cell. The concentrations for the chromosome test were 1,250, 2,500 and 5,000 ㎍/ml with metabolic activation (+S, 6 hours treatment), 1,100, 2,200 and 4,400 ㎍/ml without metabolic activation (-S, 6 hours treatment) 800, 1,600 and 3,200 ㎍/ml without metabolic activation (-S, 24 hours treatment). No significant increase in chromosome aberrations was observed at any of these concentrations both in the absence and presence of metabolic activation system. Cyclophosphamide monohydrate (CPA) and ethylmethanesulfonate (EMS) caused a significant increase in chromosome aberration. These results may be concluded that wild ginseng culture extract is not capable of inducing chromosome aberration in cultured chinese hamster lung cell regardless of metabolic activation and genotoxicity of that is negative under the present experimental condition.

• Toxicological Research
• /
• v.32 no.2
• /
• pp.89-93
• /
• 2016

Human cytochrome P450 enzymes (P450s, CYPs) are major oxidative catalysts that metabolize various xenobiotic and endogenous compounds. Many carcinogens induce cancer only after metabolic activation and P450 enzymes play an important role in this phenomenon. P450 1B1 mediates bioactivation of many procarcinogenic chemicals and carcinogenic estrogen. It catalyzes the oxidation reaction of polycyclic aromatic carbons, heterocyclic and aromatic amines, and the 4-hydroxylation reaction of $17{\beta}$-estradiol. Enhanced expression of P450 1B1 promotes cancer cell proliferation and metastasis. There are at least 25 polymorphic variants of P450 1B1 and some of these have been reported to be associated with eye diseases. In addition, P450 1B1 polymorphisms can greatly affect the metabolic activation of many procarcinogenic compounds. It is necessary to understand the relationship between metabolic activation of such substances and P450 1B1 polymorphisms in order to develop rational strategies for the prevention of its toxic effect on human health.

• Proceedings of the PSK Conference
• /
• 2003.10b
• /
• pp.195.3-196
• /
• 2003

In this study, we investigated the molecular pathways targeted by platycodin D, which could involve apoptosis in immortalized human keratinocytes (HaCaT). We demonstrated that platycodin D-mediated apoptosis of HaCaT cells exhibited representative features, including DNA fragmentation, caspase-3, caspase-8 activation, and upregulation of Fas and FasL expression, but not p53 activation. To investigate the events involved in activation-induced FasL upregulation, we have examined mRNA accumulation, protein expression, and NF-$\kappa$B activity to elucidate transcription level in the HaCaT cell line treated with platycodin D. (omitted)

• Molecular & Cellular Toxicology
• /
• v.2 no.3
• /
• pp.176-184
• /
• 2006

The controversy on genotoxicity of molinate, an herbicide, has been reported in bacterial system, and in vitro and in vivo mammalian systems. To clarify the genotoxicity of molinate, we performed bacterial gene mutation test, in vitro chromosome aberration and mouse lymphoma $tk^{+/-}$ gene assay, and in vivo micronucleus assay using bone marrow cells and peripheral reticulocytes of mice. In bacterial gene mutation assay, no mutagenicity of molinate ($12-185{\mu}g/plate$) was observed in Salmonella typhimurium TA 98, 100, 1535 and 1537 both in the absence and in the presence of S-9 metabolic activation system. The clastogenicity of molinate was observed in the presence ($102.1-408.2\;{\mu}g/mL$) of metabolic activation system in mammalian cell system using Chinese hamster lung fibroblast. However, no clastogenicity was observed in the absence ($13.6-54.3\;{\mu}g/mL$) of metabolic activation system. It is suggested that the genotoxicity of molinate was derived some metabolites by metabolic activation. Molinate was also subjected to mouse lymphoma L5178Y $tk^{+/-}$ cells using microtiter cloning technique. In the absence of S-9 mixture, mutation frequencies (MFs) were revealed $1.4-1.9{\times}10^{-4}$ with no statistical significance. However, MFs in the presence of metabolic activation system revealed $3.2-3.4{\times}10^{-4}$ with statistical significance (p<0.05). In vivo micronucleus (MN) assay using mouse bone marrow cells, molinate revealed genotoxic potential in the dose ranges of 100-398 mg/kg of molinate when administered orally. Molinate also subjected to acridine orange MN assay with mouse peripheral reticulocytes. The frequency of micronucleated reticulocytes (MNRETs) induced 48 hr after i.p. injection at a single dose of 91, 182 and 363 mg/kg of molinate was dose-dependently increased as $10.2{\pm}4.7,\;14.6{\pm}3.9\;and\;28.6{\pm}6.3\;(mean{\pm}SD\;of\;MNRETs/2,000\;reticulocytes)$ with statistical significance (p<0.05), respectively. Consequently, genotoxic potential of molinate was observed in in vitro mammalian mutagenicity systems only in the presence of metabolic activation system and in vivo MN assay using both bone marrow cells and peripheral reticulocytes in the dose ranges used in this experiment. These results suggest that metabolic activation plays a critical role to express the genotoxicity of molinate in in vitro and in vivo mammalian system.

• Molecular & Cellular Toxicology
• /
• v.2 no.4
• /
• pp.244-250
• /
• 2006

The detection of many synthetic chemicals used in industry that may pose a genetic hazard in our environment is of great concern at present. Since these substances are not limited to the original products, and enter the environment, they have become widespread environmental pollutants, thus leading to a variety of chemicals that possibly threaten the public health. In this respect, to regulate and to evaluate the chemical hazard will be important to environment and human health. The genotoxicity of 3 synthetic chemicals was evaluated in L5178Y $tk^{+/-}$ mouse lymphoma cells in vitro. 9H-carbazole (CAS No. 86-74-8) did not induce significant mutation frequencies both in the presence and absence of metabolic activation system. 1, 3-Dichloro-2-propanol (CAS No. 96-23-1) revealed a significant increase of mutation frequencies in the range of $625-373\;{\mu}g/mL$ in the absence of metabolic activation system and $157-79\;{\mu}g/mL$ in the presence of metabolic activation system. And also, fenpropathrin (CAS No. 64257-84-7) appeared the positive results only in the absence of metabolic activation system. Through the results of MLA tk assay with 3 synthetic chemicals in L5178Y cells in vitro, we may provide the important clues on the genotoxic potentials of these 3 chemicals.

• Biomolecules & Therapeutics
• /
• v.15 no.3
• /
• pp.192-198
• /
• 2007

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a major constituent of rhubarb. Although it has been claimed to have a wild spectrum of therapeutic value, its side effects, especially in human kidney cells have not been well characterized. In this study, we have carried out in vitro genetic toxicity test of emodin and microarray analysis of differentially expressed genes in response to emodin. The result of Ames test showed mutations with emodin treatment in base substitution strain TA1535 both with and without exogenous metabolic activation. Likewise, emodin showed mutations in frame shift TA98 both with and without exogenous metabolic activation. The result of COMET assay in L5178Y cells with emodin treatment showed DNA damage both with and without exogenous metabolic activation. Emodin did not increase micronuclei in CHO cells both with and without exogenous metabolic activation. 150 Genes were selected as differentially expressed genes in response to emodin by microarray analysis and these genes would be candidate biomarkers of genetic toxic action of emodin.

• Biomolecules & Therapeutics
• /
• v.15 no.3
• /
• pp.199-204
• /
• 2007

Carbamates have excellent insecticidal activities against a broad spectrum of insects. They possess knocking-down, fast-killing, and systemic effects, however, they are toxic to mammals. In this study, we have carried out in vitro genetic toxicity test of methylcarbamate and microarray analysis of differentially expressed genes in response to methylcarbamate. Methylcarbamate did not show mutations in base substitution strain TA1535 both with and without exogenous metabolic activation. Methylcarbamate did not show mutations in frame shift TA98 both with and without exogenous metabolic activation. Methylcarbamate showed DNA damage based on single cell gel/comet assay in L5178Y cells both with and without exogenous metabolic activation. Methylcarbamate did not increase micronuclei in CHO cells both with and without exogenous metabolic activation. Microarray analysis of gene expression profiles in L5178Y cells in response to methylcarbamate selected differentially expressed 132 genes that could be candidate biomarkers of genetic toxic action of methylcarbamate.

• Biomolecules & Therapeutics
• /
• v.14 no.4
• /
• pp.246-252
• /
• 2006

1,2-Dibromoethane(DBE) has been widely used as a soil fumigant, an additive to leaded gasoline and an industrial solvent. In this study, we have carried out in vitro genetic toxicity test of 1,2-dibromoethane and microarray analysis of differentially expressed genes in response to 1,2-dibromoethane. 1,2-Dibromoethane showed mutations in base substitution strain TA1535 both with and without exogenous metabolic activation. 1,2-Dibromoethane showed mutations in frame shift TA98 both with and without exogenous metabolic activation. 1,2-Dibromoethane showed DNA damage based on single cell gel/comet assay in L5178Y cells both with and without exogenous metabolic activation. 1,2-Dibromoethane increased micronuclei in CRO cells both with and without exogenous metabolic activation. Microarray analysis of gene expression profiles in L5178Y cells in response to 1,2-dibromoethane selected differentially expressed 241 genes that would be candidate biomarkers of genetic toxic action of 1,2-dibromoethane.