Coagulation protein function. III. Effect of acetaldehyde upon the activation of prothrombin.
When prothrombin is mixed with acetaldehyde (AcH), the primary metabolite of ethanol, at room temperature for 30 min, dialyzed to remove excess AcH, and then activated with Echis carinatus venom (ECV), a prolonged clotting time is observed. Similarly treated prothrombin, however, readily hydrolyzes the synthetic substrate, benzoyl-DL-arginine-beta-naphthylamide (BANA). These results suggest that AcH does not react with the catalytic site of thrombin, which is protected in the prothrombin molecule. However, it does react with susceptible sites on the prothrombin surface which remain alkylated during extensive dialysis to remove excess AcH and subsequent activation of the molecule by ECV. These alkylated sites on the newly formed thrombin molecule may inhibit or prevent the effective/efficient binding of fibrinogen at its binding sites, causing prolonged clotting times. The binding sites for accommodating fibrinogen on the thrombin molecule are apparently quite different from those that bind BANA. These data further suggest that prolonged clotting times that are reported in chronic alcoholics may be due, in part, to ready interaction of acetaldehyde with circulating prothrombin. Fibrinogen, which has been exposed to AcH and subsequently dialyzed to remove excess AcH, also responds with a prolonged clotting time in the presence of added thrombin, signifying that sites on fibrinogen that are essential for its function/conformation are susceptible to AcH.
Brecher
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A
Department of Chemistry, Bowling Green State University, OH 43403, USA.
Koterba
A P
AP
Basista
M H
MH
D000079:Acetaldehyde / Q000494:pharmacology*; D001587:Benzoylarginine-2-Naphthylamide / Q000737:chemistry; D001777:Blood Coagulation / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005340:Fibrinogen / Q000737:chemistry / Q000187:drug effects; D005470:Fluorometry; D006801:Humans; D006868:Hydrolysis; D011516:Prothrombin / Q000502:physiology*; D013917:Thrombin / Q000502:physiology; D014757:Viper Venoms / Q000633:toxicity
D002492:Central Nervous System Depressants; D014757:Viper Venoms; D001587:Benzoylarginine-2-Naphthylamide; D000431:Ethanol; D011516:Prothrombin; D005340:Fibrinogen; D013917:Thrombin; D000079:Acetaldehyde