Lap. Hoogenboom et al., BIOTRANSFORMATION OF FURALTADONE BY PIG HEPATOCYTES AND SALMONELLA-TYPHIMURIUM TA-100 BACTERIA, AND THE FORMATION OF PROTEIN-BOUND METABOLITES, Xenobiotica, 24(8), 1994, pp. 713-727
1. The major metabolite resulting from the biotransformation of furalt
adone (5-morpholinomethyl- 3-[5-nitrofurfurylidene-amino]-2-oxazolidin
one) by pig hepatocytes was shown to result from the N-oxidation of th
e tertiary nitrogen in the morpholino-ring, leaving the nitrofuran rin
g unchanged. 2. No evidence could be obtained for the formation of an
open-chain cyano-metabolite, a minor metabolite in the case of the rel
ated nitrofuran drug furazolidone 5-nitro-2-furfurylidene)-3-amino-2-o
xazolidinone). This metabolite was the major metabolite, following inc
ubation of furaltadone and furazolidone with Salmonella typhimurium ba
cteria. 3. The N-oxide was not further metabolized by pig hepatocytes
or bacteria, and gave negative test results in the Ames-test (TA 100,
no S9-mix) at the highest tested dose of 1 mu g/plate. Furaltadone gav
e a positive result at 10 ng/plate. 4. The biotransformation of both d
rugs by pig hepatocytes and bacteria resulted in the formation of prot
ein-bound metabolites, with no clear quantitative differences between
the two drugs. The intact 3-amino-2-oxazolidinone (AOZ) and 5-morpholi
nomethyl-3-amino-2-oxazolidinone (AMOZ) side-chains of furazolidone an
d furaltadone, respectively, could be released from these metabolites
by mild acid treatment. 5. Hepatocytes incubated with the AMOZ side-ch
ain of furaltadone showed a decreased monoamine oxidase activity at hi
gh dose levels (IC50 3.7 mM), whereas exposure to the AOZ side-chain o
f furazolidone resulted in a clear inhibition at 10 000-fold lower con
centrations (IC50 0.5 mu M). In the presence of 1% dimethylsulphoxide
(DMSO), the MAO-inhibition by AMOZ and especially AOZ was remarkably r
educed. 6. It is concluded that protein-bound metabolites containing a
n intact and releasable side-chain might be present in tissues of anim
als treated with furaltadone. However, these residues might be of less
toxicological concern than those of furazolidone.