Safety evaluation of certain food additives - ipcs inchem

FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS 495
with phenobarbital pretreatment. Conversely, N-octylimidazole pretreatment
decreased the level of covalent binding of the 14 C label to proteins and DNA in the
liver, lung and kidney. Increased and decreased protein binding and hepatotoxicity
measured as serum GPT levels were observed in rats pretreated with phenobarbital
and N-octylimidazole, respectively. 3-Methylcholanthrene or piperonyl butoxide
pretreatment did not affect either covalent binding or hepatotoxicity. These results
provide evidence that bioactivation of 2-methylfuran by a CYP system is a
prerequisite for tissue necrosis in rats (Ravindranath et al., 1986).
In a study examining GSH and cysteine conjugation on the toxic potential
of 2-methylfuran, male Sprague-Dawley rats were treated subcutaneously with a
900 mg/kg bw dose of buthionine sulfoximine 1.5 h prior to intraperitoneal
administration of 100 mg [ 14 C]2-methylfuran/kg bw prepared in sesame oil. Marked
decreases in covalent DNA and protein binding in the liver and reduced
hepatotoxicity, as indicated by lower serum GPT levels, were observed. Buthionine
sulfoximine treatment revealed a transient increase in plasma cysteine levels,
concurrent with a decrease in GSH levels. However, administration of 100 mg
2-methylfuran/kg bw 1.5 h after buthionine sulfoximine administration significantly
reduced plasma cysteine levels and increased (20%) urinary elimination of
2-methylfuran-labelled metabolites compared with the control group ([ 14 C]2methylfuran
only). Subcutaneous pretreatment with diethylmaleate, a depletor of
liver GSH, at 0.4 ml/kg bw increased binding to liver proteins and increased
hepatotoxicity, as indicated by a rise in serum GPT levels compared with rats that
received only 2-methylfuran. Subcutaneous pretreatment of rats with GSH
synthesis promoter L-2-oxothiazolidine-4-carboxylate at a dose of 1000 mg/kg bw
resulted in a marked increase of covalent protein binding in the liver and potentiated
hepatotoxicity (increased serum GPT levels compared with rats that received only
2-methylfuran). When rats were pretreated with both buthionine sulfoximine and
L-2-oxothiazolidine-4-carboxylate, a marked decrease in covalent protein binding
in the liver and hepatotoxicity, as indicated by a reduction in serum GPT levels, was
observed. No unchanged 2-methylfuran was observed in the urine, indicating that
pretreatment did not inhibit metabolic processes (Ravindranath & Boyd, 1991). The
authors proposed that buthionine sulfoximine pretreatment indirectly aids in the
detoxication of 2-methylfuran through a reduction of GSH supply and an increase
in the availability of cysteine, which forms a more stable conjugate with
acetylacrolein (Esterbauer et al., 1976; Ravindranath & Boyd, 1991).
Adult male Swiss albino mice (10–15 per group) were administered
2-ethylfuran (commercial grade, No. 1489) at 200 mg/kg bw in sesame oil via
intraperitoneal injection with or without phenobarbital, piperonyl butoxide or
cobalt(II) chloride pretreatment. The mortality rates were 1/10, 2/10, 3/15 and 2/11
for the untreated, phenobarbital pretreatment, piperonyl butoxide pretreatment and
cobalt(II) chloride pretreatment groups, respectively. 2-Ethylfuran produced a
moderate necrosis of the liver and mild to moderate necrosis of the kidneys. The
kidney necrosis was described as a coagulative lesion of the proximal convoluted
tubules of the outer cortex, without damage to the glomerular or medullary cells.
Piperonyl butoxide and cobalt(II) chloride decreased the severity of necrosis in the
liver and kidney (McMurtry & Mitchell, 1977).