Abstract：
:Liver mitochondrial low-Km aldehyde dehydrogenase (ALDH2, EC 1.2.1.3), the isoform responsible for the conversion of acetaldehyde to acetate, is inhibited by the sulfoxide bioactivation products of Et2NC(O)SMe (from the alcohol aversion drug disulfiram), Pr2NC(O)SEt (the herbicide S-ethyl N,N-dipropylthiocarbamate), and BuNHC(O)SMe (from the fungicide benomyl). This study tested the hypothesis that bioactivated BuNHC(O)SMe, the most potent of these thiocarbamates, is a selective carbamoylating agent for ALDH2 of mouse liver in vivo and in vitro. [14C]BuNHC(O)SMe administered i.p. to mice labeled one principal mitochondrial protein, which cochromatographed with ALDH activity by in-gel assay after isoelectric focusing. The labeled protein was isolated by isoelectric focusing (pI 6.1) and SDS-PAGE (54 kDa) and identified as ALDH2 by sequencing of peptides from a tryptic digest. In vivo at 1.5 mg/kg, enzyme inhibition was 80%, and ALDH2 was the only mitochondrial protein labeled extensively, illustrating the outstanding potency and specificity. ALDH2 also was labeled upon incubation of mouse liver mitochondria with [14C]BuNH-C(O)SMe in the presence of microsomes (P450) and NADPH. In contrast, under similar conditions, [14C]Pr2NC(O)SEt sulfoxide labeled primarily two other proteins at approximately 58 and approximately 61 kDa, establishing a very different selectivity for the two sulfoxides. These findings are of interest relative to selective inhibitors and carbamoylating agents for ALDH2 and to alcohol aversion upon exposure to herbicides and fungicides.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Staub RE,Quistad GB,Casida JEdoi
10.1016/s0006-2952(99)00239-7subject
Has Abstractpub_date
1999-11-01 00:00:00pages
1467-73issue
9eissn
0006-2952issn
1873-2968pii
S0006-2952(99)00239-7journal_volume
58pub_type
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