Noscapine-induced polyploidy in vitro.
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.
Mitchell
I D
ID
SmithKline Beecham Pharmaceuticals, Welwyn, Hertfordshire, UK.
Carlton
J B
JB
Chan
M Y
MY
Robinson
A
A
Sunderland
J
J
D001973:Bromodeoxyuridine; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002875:Chromosomes / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D004121:Dimethyl Sulfoxide; D006801:Humans; D008861:Microsomes; D009153:Mutagens / Q000633:toxicity*; D009665:Noscapine / Q000633:toxicity*; D011123:Polyploidy; D012997:Solvents; D013601:T-Lymphocytes / Q000187:drug effects; D013997:Time Factors
D003470:Culture Media; D009153:Mutagens; D012997:Solvents; D009665:Noscapine; D001973:Bromodeoxyuridine; D004121:Dimethyl Sulfoxide