Genetic toxicology assessment of HI-6 dichloride

Abstract

The oxime HI‐6 dichloride [1‐(2 hydroxyiminomethyl‐1‐pyridino)‐3‐(4‐carbamoyl‐1‐pyridino)‐2‐oxapropane dichloride monohydrate] has shown to be a potent reactivator of cholinesterase activity and may have efficacy for the treatment of organo‐phosphate intoxication [SIPRI, 1976; Schenk et al.; Arch Toxicol 36:71–81, 1976]. As part of a preclinical safety assessment program, the genetic toxicology of HI‐6 dichloride was evaluated in a series of assays designed to measure induction of gene mutations and chromosomal aberrations. HI‐6 dichloride gave negative responses in the Salmonella mutagenicity assay and in the CHO/HGPRT gene mutation assay. Dose‐dependent increases in the frequency of chromosomal aberrations were noted when HI‐6 dichloride was tested in cultured CHO cells and in cultured human peripheral blood lymphocytes. The mouse lymphoma gene mutation assay, reputed to measure both gene mutations and chromosomal deletions, was negative in the absence of metabolic activation. Depending on the criteria employed, a negative or equivocal response was seen in the presence of rat liver‐derived S‐9 mix. An in vivo rat bone marrow metaphase assay performed to further investigate the in vitro clastogenic responses was negative. The results from these studies indicate that HI‐6 dichloride does not induce gene mutations in vitro; however, it is clastogenic in vitro but does not appear to be clastogenic in vivo. © 1996 Wiley‐Liss, Inc.

Cytotoxicity and genotoxicity evaluation of antidote oxime HI-6 tested on eight cell lines of human and rodent origin

“…Values represent means ± SE of 50 cells (comets) obtained in one representative experiment (2 or 3 experiments were performed with each cell line). responsible for the induction of chromosome damage found in the study (Putman et al 1996). Published results indicate that HI-6 does not induce gene mutations in vitro.…”

“…So far we have not enough information about HI-6 cytotoxicity and genotoxicity. As it was published earlier, HI-6 was not genotoxic using tests on Salmonella typhimurium, mouse lymphoma and Chinese hamster ovary (CHO) cells, both with and without metabolic activation (Putman et al 1996). In vivo clastogenicity evaluation on rats was also negative, however, HI-6 induced significant amount of chromosome aberrations in vitro in CHO cells.…”

“…Cytotoxicity and genotoxicity of HI-6 was previously studied by Putman et al (1996). In this study a HI-6 dichloride was tested in a battery of assays to measure its potential to induce gene mutations and chromosomal aberrations.…”