Human CYP2E1-dependent mutagenicity of mono- and dichlorobiphenyls in Chinese hamster (V79)-derived cells

Zhang, Chiteng; Lai, Yanmei; Jin, Guifang; Glatt, Hansruedi; Wei, Qiujing; Liu, Yungang

doi:10.1016/j.chemosphere.2015.10.083

Cited by 11 publications

(13 citation statements)

References 30 publications

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“…This assay detects forward mutations at the Hprt locus, as manifested by an acquisition of resistance to 6‐thioguanine. We followed the procedure described recently (Zhang et al ; Liu et al ). Briefly, 1.5 × 10 6 cells were inoculated in 30 mL medium in each 250‐cm 2 flask.…”

Section: Methodsmentioning

confidence: 99%

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Mutagenic Activity of N‐Nitrosodiethylamine in Cell Lines Expressing Human CYP2E1—Adequacy of Dimethylsulfoxide as Solvent

Jin

Cai

et al. 2018

Environ and Mol Mutagen

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Human CYP2E1 metabolizes many xenobiotics of low‐molecular weight, thereby activating various promutagens/procarcinogens. In toxicological studies in vitro, dimethylsulfoxide (DMSO) is a common vehicle for organic compounds. However, it was observed to potently inhibit CYP2E1 activity. We were interested in whether it affects CYP2E1‐dependent mutagenic responses. In this study, N‐nitrosodiethylamine (NDEA), which is soluble in both water and DMSO, was used as a model promutagen. It induced Hprt gene mutations and micronuclei in a Chinese hamster V79‐derived cell line expressing both human CYP2E1 and sulfotransferase (SULT) 1A1 (V79‐hCYP2E1‐hSULT1A1) even at low‐micromolar concentrations, but was inactive in parental V79 cells. Mutagenicity of NDEA was also observed in a recombinant V79‐hCYP2E1 cell line that expresses human CYP2E1 at a lower level. NDEA induced micronuclei in human L‐02 hepatocytes which expressed CYP2E1 even more weakly. DMSO did not modify NDEA‐induced gene mutations or micronuclei, up to 0.2% (v:v, the highest noncytotoxic concentration) in V79‐hCYP2E1‐hSULT1A1 cells. In parental V79‐Mz cells, NDEA induced micronuclei with Aroclor 1254‐induced rat liver S9 mix, and this effect was unaffected by DMSO up to 0.2%. However, it inhibited the effect of NDEA in L‐02 (by 44%) and V79‐hCYP2E1 cells (by 70%) at 0.2%, with the effects of NDEA remaining statistically significant. No effect of DMSO was observed on CYP2E1 protein expression in V79‐hCYP2E1‐hSULT1A1 or its mRNA transcripts in each cell line. We conclude that DMSO may not significantly affect CYP2E1‐dependent mutagenic effects, at concentrations up to 0.2% in cells with relatively high CYP2E1 expression. Environ. Mol. Mutagen. 60:214–226, 2019. © 2018 Wiley Periodicals, Inc.

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Section: Methodsmentioning

confidence: 99%

“…The micronucleus test was conducted as recently described (Zhang et al ; Liu et al ). V79‐hCYP2E1‐hSULT1A1 or L‐02 cells were inoculated at the density of 3 × 10 5 per 12.5‐cm 2 flask.…”

Section: Methodsmentioning

confidence: 99%

Mutagenic Activity of N‐Nitrosodiethylamine in Cell Lines Expressing Human CYP2E1—Adequacy of Dimethylsulfoxide as Solvent

Jin

Cai

et al. 2018

Environ and Mol Mutagen

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“…The cytotoxicity of each PCB or ethyl methanesulfonate (a known mutagen as the positive control for the micronucleus test) was determined in each cell line using disulfonated tetrazolium salt (CCK‐8), a chromogenic indicator for NADH and cell viability, using a well‐established method [Ishiyama et al, ]. The exposure‐recovery regimen of 12 h/12 h was applied in accordance to the micronucleus test in V79 and V79‐Mz cells to evaluate cytotoxicity, as described in a recent report [Zhang et al, ]; and that of 24 h/24 h was used for determining the cytotoxicity of test compounds in HepG2 cells, whose doubling time is about 24 h. Six replicates were used for each treatment. The final concentration of DMSO, the vehicle for each PCB, was limited to 0.1% (v:v).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we have observed potent mutagenicity of some di‐, tri‐, and tetrachlorobiphenyls in Chinese hamster V79‐derived cells genetically engineered for expressing both human CYP2E1 and SULT1A1 (cell line V79‐hCYP2E1‐hSULT1A1), as indicated by the induction of micronuclei and gene mutations; while in the parental V79‐Mz cells, these PCBs were inactive. Human CYP2E1 is confirmed to be responsible for the mutagenicity of PCBs, while other CYP enzymes (1A1, 1B1, 1A2, and 3A4) are not substantially involved in activating PCBs to mutagenic metabolites [Zhang et al, ; Liu et al, ]. More recently, a cell line subcloned from V79 cells, named V79‐Mz, which had served as the parental cells for the establishment of a series of V79‐derived cell lines expressing various biotransformation enzymes (including V79‐hCYP2E1‐hSULT1A1), became available in our laboratory.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, a cell line subcloned from V79 cells, named V79‐Mz, which had served as the parental cells for the establishment of a series of V79‐derived cell lines expressing various biotransformation enzymes (including V79‐hCYP2E1‐hSULT1A1), became available in our laboratory. Therefore, we tested the mutagenicity of several dichlorobiphenyls in V79‐Mz cells; the results indicated active induction of micronuclei, unlike the negative results in V79 cells [Zhang et al, ], with potencies lower than that in V79‐hCYP2E1‐hSULT1A1 cells [Zhang et al, ; Liu et al, ]. We were then interested in the metabolism‐independent genotoxicity of PCBs in mammalian cells and the related structure–activity relationships.…”

Section: Introductionmentioning

confidence: 99%

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Induction of micronuclei and cell cycle arrest by some tri‐ and tetrachlorobiphenyls in mammalian cells deficient in xenobiotic‐metabolizing enzymes

Wang

Wei

et al. 2017

Environ and Mol Mutagen

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Polychlorinated biphenyls (PCBs) are persistent organic pollutants with continued public health concerns. The lower chlorinated biphenyls are supposed to be mutagenic following metabolic activation. However, in a preliminary study, we recently observed induction of micronuclei by several PCBs in a subclone of Chinese hamster V79 cell line, V79-Mz, which is deficient in xenobiotic-metabolizing enzyme activities. In this study, metabolism-free genotoxicity of PCBs was investigated, using 10 tri- and tetrachlorobiphenyls, in V79, V79-Mz, and human hepatoma (HepG2) cell lines. Among the four tetrachlorobiphenyls, 2,4,4',5- and 2,3'4,4'-tetrachlorobiphenyl-both having a noncoplanar configuration-induced micronuclei in V79-Mz cells, while their coplanar analogs 3,4,4',5- and 3,3',4,4'-tetrachlorobiphenyl were inactive. Furthermore, 2,3,3'- (PCB 20) and 2,3,4'-trichlorobiphenyl (PCB 22) started to induce micronuclei in V79-Mz cells at 10 μM and higher concentrations, demonstrating more potent effects than observed with 2,2',3-, 2,2',4-, 2,2',5, and 2,4,4'-trichlorobiphenyl. As representative compounds, PCB 20 and 22 induced micronuclei in relatively high concentrations in HepG2 cells (p53-proficient), though they did not induce Hprt gene mutations in V79-Mz cells. PCB 20 and 22 increased mitotic index and induced cell cycle arrest at the G2/M phase, with effects more potent in V79-Mz than in V79 cells. This study suggests that 2,3,4'- and 2,3,3'-substituted PCBs are micronuclei inducers and G2/M arresters among a number of trichlorobiphenyls in mammalian cell lines, though with potency lower than that observed recently in V79-derived cells expressing human CYP2E1. Similarly, some noncoplanar tetrachlorobiphenyls possess metabolism-independent chromosome-damaging potentials. Environ. Mol. Mutagen. 58:199-208, 2017. © 2017 Wiley Periodicals, Inc.

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Potent mutagenicity of some non-planar tri- and tetrachlorinated biphenyls in mammalian cells, human CYP2E1 being a major activating enzyme

Liu

Jia

et al. 2016

Arch Toxicol

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Polychlorinated biphenyls (PCBs) have been classified as human carcinogens. Mutagenicity of lower chlorinated biphenyls as well as activation of transcription factors by some other congeners may contribute to the carcinogenicity of PCBs. Recently, we reported that human CYP2E1 activates mono- and dichlorobiphenyls to mutagens. However, mutagenicity of other PCBs and the involvement of other CYPs remained unknown. In this study, Chinese hamster V79-derived cell lines genetically engineered for expression of individual human CYP enzymes and a human hepatocyte (L-02) line endogenously expressing various CYPs were used to determine the activities of several tri- and tetrachlorobiphenyls to induce micronuclei and gene mutations. 2,3,4'-Trichlorobiphenyl, 2,3,3'-trichlorobiphenyl, 2,4,4',5-tetrachlorobiphenyl and 2,2',5,5'-tetrachlorobiphenyl efficiently induced micronuclei and/or gene mutations in V79-derived cells at low micromolar concentrations, depending on human CYP2E1, while they were inactive in parental V79-Mz cells and weakly positive or inactive in V79-derived cells expressing human CYP1A1, 1A2, 1B1 or 3A4. The induction of gene mutations in human CYP2E1-expressing V79 cells by 2,3,4'-trichlorobiphenyl and 2,4,4',5-tetrachlorobiphenyl was more potent than that of N-nitrosodimethylamine, a strong carcinogen activated by CYP2E1. As representative PCB compounds, 2,3,3'-trichlorobiphenyl and 2,3,4'-trichlorobiphenyl induced micronuclei in L-02 cells, and this effect was blocked by specific CYP2E1 inhibition, wherein the effects of benzo[a]pyrene and aflatoxin B (activated by some CYPs other than CYP2E1) were unaffected. This study demonstrates that some non-planar tri- and tetrachlorobiphenyls are potent mutagens in mammalian cells-more potent than previously tested mono- and dichlorobiphenyls-and that among several human CYP enzymes, CYP2E1 is most efficient in activating these environmental contaminants.

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Human CYP2E1-dependent mutagenicity of mono- and dichlorobiphenyls in Chinese hamster (V79)-derived cells

Cited by 11 publications

References 30 publications

Mutagenic Activity of N‐Nitrosodiethylamine in Cell Lines Expressing Human CYP2E1—Adequacy of Dimethylsulfoxide as Solvent

Mutagenic Activity of N‐Nitrosodiethylamine in Cell Lines Expressing Human CYP2E1—Adequacy of Dimethylsulfoxide as Solvent

Induction of micronuclei and cell cycle arrest by some tri‐ and tetrachlorobiphenyls in mammalian cells deficient in xenobiotic‐metabolizing enzymes

Potent mutagenicity of some non-planar tri- and tetrachlorinated biphenyls in mammalian cells, human CYP2E1 being a major activating enzyme

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