Safety evaluation of certain food additives - ipcs inchem

FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS 493
1-hydroxybenzbromarone was 2.12 in the plasma and 7.32 in the urine. These
metabolic data support the conclusion that alkyl-substituted furan and benzofuran
derivatives undergo side-chain oxidation to yield the corresponding alcohol
metabolite, which can be excreted as the glucuronic acid conjugate or oxidized to
the corresponding ketone, followed by excretion in the urine.
Unsubstituted and short-chain alkyl-substituted furans have also been
shown to undergo ring epoxidation in the liver by mixed-function oxidases. Epoxysubstituted
furans have been reported to undergo ring opening to yield reactive 2ene-1,4-dicarbonyl
intermediates (see example in Figure 2) that can be conjugated
with GSH and readily eliminated in the urine or, at relatively high concentrations,
react with proteins and DNA to form adducts.
Initial in vitro experiments in rat microsomal preparations suggested that high
concentrations of alkyl-substituted furans are partly metabolized to reactive
acetylacrolein 1 -type intermediates (Ravindranath et al., 1983, 1984). Acetylacrolein
is a potent microsomal mixed-function oxidase inhibitor that has been reported to
bond covalently and irreversibly to the oxidizing enzyme, thus inactivating it
(Ravindranath & Boyd, 1985).
Significant protein binding (>55 nmol/mg protein) was reported when 10
mmol [ 14 C]2-methylfuran/l was incubated with rat hepatic microsomes in the
presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and
oxygen (Ravindranath & Boyd, 1985). In the absence of oxygen or NADPH, little
binding was observed (80 nmol/mg protein) was also reported when Sprague-Dawley rats
were pretreated with phenobarbital, a CYP inducer, whereas decreased or no
protein binding was observed in the presence of piperonyl butoxide and N-octyl
imidazole, both of which are inhibitors of CYPs. The maximum rate (Vmax) and
Michaelis-Menten constant (Km) for 2-methylfuran metabolism in phenobarbitalpretreated
rats were 0.81 μmol/2 mg microsomal protein per minute and
0.463 mmol/l, respectively; in rats without phenobarbital pretreatment, they were
0.53 μmol/2 mg microsomal protein per minute and 1.417 mmol/l, respectively.
These data suggest that 2-methylfuran undergoes CYP-mediated oxidation to yield
a reactive metabolite (i.e. acetylacrolein) that binds covalently to protein.
In the same study, when acetylacrolein at 0.25 mmol/l (24.5 μg/ml) was
added to the incubation mixture, microsomal metabolism of 2-methylfuran was
almost completely inhibited (covalent binding was 1.5% of the control incubation).
At a concentration of 0.5 mmol acetylacrolein/l (49.1 μg/ml), no metabolism of
2-methylfuran was detectable, suggesting that acetylacrolein inhibits CYPmediated
oxidation, probably through direct covalent bonding with the enzyme.
Thus, 2-methylfuran is a suicide substrate for CYP. Conjugation of the reactive
1
H
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