Effects of prolonged disulfiram treatment on plasma dopamine-beta-hydroxylase activity in rhesus monkeys.

In 1948 two Danish physicians became ill upon drinking after ingesting disulfiram. Their subsequent report on drug sensitizing the organism to ethyl alcohol (1) led to disulfiram's introduction for the treatment of alcoholism (2). The drug produces an aversion to ethanol by inhibiting aidehyde dehydrogenase (3-5), leading to high blood levels soon after ingestion. Ethanol, oxidized to by dehydrogenase (6), cannot be further oxidized when aidehyde dehydrogenase is inhibited by disulfiram. The resulting acetaldehyde syndrome is characterized by vasodilation, orthostatic hypotension and a throbbing sensation with pulsating headache (7). These symptoms, which can be mediated by the sympathetic nervous system, apparently result from the elevation of blood acetaldehyde, an effective catecholamine releaser (8, 9). Disulfiram alone can have side effects of fatigue, tremor, reduced sexual potency, headache and dizziness (10), and these effects can also be mediated by sympathetic nervous system dysfunction. Although disulfiram is a potent inhibitor (K i = 10 -7) of aidehyde dehydrogenase (5), it also inhibits the enzyme dopamine-•-hydroxylase (DB•I), somewhat less effectively (K i = 10-6), by chelating the enzymebound copper ion essential to •)•3i• activity (11). D•3i• converts dopamine to norepinephrine (12, 13) and is present in nerve endings of the sympathetic nervous system, where it is released along with norepinephrine (14-16).