Cytotoxic, DNA-damaging and mutagenic properties of 2,6-dimethoxy-1,4-benzoquinone, formed by dimethophrine-nitrite interaction.
In conditions similar to those occurring in the stomach, the sympathomimetic drug dimethophrine was found to react with nitrite yielding 2,6-dimethoxy-1,4-benzoquinone (DMBQ). The in vitro and in vivo studies carried out to evaluate the capability of DMBQ to produce cytotoxic and genotoxic effects provided the following results. A dose-related reduction of V79 cells plating efficiency was observed for DMBQ concentrations ranging from 10 to 80 microM; a similar reduction in the fraction of viable cells excluding trypan blue occurred after exposure to 4-fold higher concentrations. A dose-dependent amount of DNA fragmentation was revealed by the alkaline elution technique either in V79 cells exposed to DMBQ concentrations ranging from 10 to 80 microM or in kidney, gastric mucosa and brain of rats treated with single p.o. doses ranging from 33 to 300 mg/kg. Both in vitro and in vivo DNA lesions were largely repaired within 24 hr, but their promutagenic character was demonstrated by the induction of 6-thioguanine-resistance in V79 cells. Primary cultures of rat hepatocytes displayed a greater resistance to the cytotoxic and DNA-damaging activities of DMBQ, and did not exhibit a clear evidence of DNA repair synthesis. Similarly, DNA fragmentation was practically undetectable in the rat liver. Therefore, DMBQ should be considered as a direct-acting genotoxic chemical which is metabolized to less, or nonreactive, species. These findings suggest that DMBQ could produce genotoxic effects in patients taking dimethophrine.
Brambilla
G
G
Institute of Pharmacology, University of Genoa, Italy.
Robbiano
L
L
Cajelli
E
E
Martelli
A
A
Turmolini
F
F
Mazzei
M
M
D000818:Animals; D016227:Benzoquinones; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair; D004983:Ethanolamines / Q000378:metabolism*; D008297:Male; D009153:Mutagens; D009573:Nitrites / Q000378:metabolism*; D011809:Quinones / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D016227:Benzoquinones; D004983:Ethanolamines; D009153:Mutagens; D009573:Nitrites; D011809:Quinones; C030511:2,6-dimethoxy-1,4-benzoquinone; D004247:DNA; C100197:dimethophrine