Structure vs. activity in the sulfonylurea-mediated disulfiram-ethanol reaction.
The oral hypoglycemic agents, chlorpropamide (CP) and tolbutamide (TB) are known to elicit a clinical disulfiram-ethanol reaction (DER) when consumed with alcohol. In rats, this DER is manifested in vivo by the elevation of blood acetaldehyde (AcH) levels, a consequence of the inhibition of hepatic aldehyde dehydrogenase (AIDH). Administration of CP or TB to rats (1.0 mmol/kg, IP), followed by ethanol one hour before sacrifice, raised blood AcH levels 12- and 2-times that of control animals, respectively for CP and TB when measured at 3 hours, and 20-fold and 8-fold at 16 hours post drug administration. CP and TB had no effect on AIDH activity when incubated with either intact or osmotically disrupted rat liver mitochondria, indicating that a metabolite of CP or TB is responsible for the inhibition of AIDH in vivo. Hydrolysis products of CP, the 2'-hydroxylated products of CP, tolpropamide and tolethamide, or the 3'-hydroxylated analogs of CP and tolpropamide, were uniformly inactive in elevating ethanol-derived blood AcH. Pretreatment of rats with 3-amino-1,2,4-triazole or SKF-525A had no effect on the elevation of blood AcH mediated by CP or TB, while phenobarbital pretreatment decreased blood AcH by 69%. Although our results clearly indicated that side chain hydroxylation and subsequent oxidation do not play a role in AIDH inhibition by CP or TB, the nature of the side chain attached to the sulfonylurea moiety appears to influence this inhibitory activity in vivo. Thus, the order of activity in the homologous series was, chlorpropamide greater than chlorbutamide greater than chlorethamide much greater than chlormethamide, chlorisopropamide = 0.
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D002747:Chlorpropamide / Q000378:metabolism / Q000494:pharmacology*; D004221:Disulfiram / Q000494:pharmacology*; D000431:Ethanol / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014044:Tolbutamide / Q000378:metabolism / Q000494:pharmacology*
D000431:Ethanol; D014044:Tolbutamide; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram; D002747:Chlorpropamide