Noscapine-induced polyploidy in vitro

Abstract

The conditions under which noscapine causes high levels of polyploidy in vitro in human lymphocytes were investigated to try to determine its mode of action and to assess whether it was likely to be a genotoxic hazard when used as an antitussive agent. Irrespective of duration of treatment or type of medium, there seemed to be a threshold for polyploidy induction between 15.0 and 30.0 micrograms/ml and a maximum between 100.0 and 150.0 micrograms/ml noscapine. High levels (10.0-20.0%) of noscapine-induced polyploidy were never found with 4 h treatments or with RPMI 1640 medium plus 15% (v/v) foetal calf serum; the use of Iscove's modified Dulbecco's medium and 24 h treatments were needed. The reasons for these observations seemed to be the faster cell division and greater sensitivity of cells grown in Iscove's medium. There was conflicting evidence about the mechanism of polyploidy induction by noscapine; either spindle damage or cell fusion remain as possibilities. The need for prolonged exposure and the precise nutritional requirements suggest that a short exposure, albeit at high concentration, in the upper gastro-intestinal tract is unlikely to be a hazard for humans. Furthermore, evidence of a threshold at approximately 20 micrograms/ml plus the virtual elimination of noscapine-induced polyploidy by microsomal metabolism (S9 mix) together with published metabolic data imply that the low-level systemic exposure after absorption may well not be hazardous. We conclude that the use of noscapine in cough mixtures does not pose a significant potential hazard for humans.

Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells

“…Karlsson et al (10) and Mourey et al (11) described high-affinity, saturable, and stereo-specific binding sites for noscapine in Guinea pig brain homogenates. In addition, noscapine has been shown to have low toxicity (7)(8)(9), although there are some reports of aneuploidy produced in cell cultures (12,13). Additionally, noscapine has been used in humans orally, and the metabolic fate, bioavailability, and pharmacokinetics of noscapine by oral administration are relatively well studied (9,14,15).…”

Kinetics in Genotoxicity—Nuisance or Necessity?

“…This can be shown in the case of noscapine where the sensitive period, namely mitosis, is of relatively short duration, providing only a small pool of susceptible cells within a certain time interval. Here four hours of exposure does not increase the proportion of polyploid cells significantly J. P. Seiler while a 24-hour exposure to much lower concentrations does (1).…”

Development of screening tests for aneuploidy induction by environmental pollutants.

“…Chemicals of environmental significance will be tested with the simplified screening procedure, such as noscapine, tear gas, and methyl vinyl sulphone, which have already been found positive in vitro (24)(25)(26), industrial solvents and pesticides, e.g., benomyl, which has been labeled as a potential mutagen by the CEC based on in vitro and in vivo data (27,28). …”