In:
Environmental and Molecular Mutagenesis, Wiley, Vol. 60, No. 3 ( 2019-04), p. 214-226
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0893-6692
,
1098-2280
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
1497682-1
SSG:
12
