Association of quinone-induced platelet anti-aggregation with cytotoxicity.
Various anti-platelet drugs, including quinones, are being investigated as potential treatments for cardiovascular disease because of their ability to prevent excessive platelet aggregation. In the present investigation 3 naphthoquinones (2,3-dimethoxy-1,4-naphthoquinone [DMNQ], menadione, and 1,4-naphthoquinone [4-NQ]) were compared for their abilities to inhibit platelet aggregation, deplete glutathione (GSH) and protein thiols, and cause cytotoxicity. Platelet-rich plasma, isolated from Sprague-Dawley rats, was used for all experiments. The relative potency of the 3 quinones to inhibit platelet aggregation, deplete intracellular GSH and protein thiols, and cause cytotoxicity was 1,4-NQ > menadione >> DMNQ. Experiments using 2 thiol-modifying agents, dithiothreitol (DTT) and 1-chloro-2,4-dintrobenzene (CDNB), confirmed the key roles for GSH in quinone-induced platelet anti-aggregation and for protein thiols in quinone-induced cytotoxicity. Furthermore, the anti-aggregative effects of a group of 12 additional quinone derivatives were positively correlated with their ability to cause platelet cytotoxicity. Quinones that had a weak anti-aggregative effect did not induce cytotoxicity (measured as LDH leakage), whereas quinones that had a potent anti-aggregative effect resulted in significant LDH leakage (84-96%). In one instance, however, p-chloranil demonstrated a potent anti-aggregative effect, but did not induce significant LDH leakage. This can be explained by the inability of p-chloranil to deplete protein thiols, even though intracellular GSH levels decreased rapidly. These results suggest that quinones that deplete GSH in platelets demonstrate a marked anti-aggregative effect. If this anti-aggregative effect is subsequently followed by depletion of protein thiols, cytotoxicity results.
Kim
S R
SR
College of Pharmacy, Seoul National University, Shinrim-dong San 56-1, Seoul 151-742, Korea.
Lee
J Y
JY
Lee
M Y
MY
Chung
S M
SM
Bae
O N
ON
Chung
J H
JH
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002703:Chloranil / Q000494:pharmacology; D004137:Dinitrochlorobenzene / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009285:Naphthoquinones / Q000633:toxicity*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014812:Vitamin K / Q000633:toxicity
D004137:Dinitrochlorobenzene; D009285:Naphthoquinones; D011506:Proteins; D013438:Sulfhydryl Compounds; D002703:Chloranil; D014812:Vitamin K; C063002:2,3-dimethoxy-1,4-naphthoquinone; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; C035342:1,4-naphthoquinone; D004229:Dithiothreitol