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EC number: 246-562-2
CAS number: 25013-15-4
A study was conducted to determine the
metabolism of the test substance in rats by investigating urinary
metabolites after injection of different doses. Male Wistar rats
received the test substance by single intraperitoneal injection in three
different experiments. In the first, the test substance dissolved in
olive oil was administered at 50, 250, 500 and 1000 mg/kg bw. Four rats
were sacrificed after 12 h at each dose level and three rats at the dose
levels of 50, 250 or 500 mg/kg bw after 23 h. In the second experiment,
rats were given the test substance (500 mg/kg bw in olive oil),
1-phenylimidazole (50 mg/kg bw in DMSO) or both. The control rats
received olive oil or DMSO alone. 1-Phenylimidazole and DMSO were
administered 1.5 h before the test substance. Four rats of each group
were sacrificed 12 h after injection of the test substance and 3 in each
group after 23 h. In the third experiment, rats were exposed to PCBs
(500 mg/kg bw in olive oil), test substance (500 mg/kg bw in olive oil)
or both Controls received olive oil only. The dose of PCB was given 5 d
before the test substance. Three animals in each group were sacrificed
23 h after injection of the test substance. Urine was collected during
the exposure from all rats in all groups. The urinary metabolites
analysed were: thioesters, p-methylmandelic acid,
p-methylphenylglyoxylic acid, the glycine conjugates of p-methylbenzoic
acid, p-methylphenylacetic acid and p-vinylbenzoic acid. The role of
cytochrome P-450 in the formation of the metabolites was studied by
inhibiting its catalytic activity.The
highest excretion rate was obtained with doses of 50, 250 and 500 mg/kg
bw already within the first 6 h. However, the dose of 500 mg/kg bw did
not increase the excretion rates of these metabolites compared to the
dose of 250 mg/kg bw, suggesting that the metabolic pathways begin to be
saturated with the amount of 250 mg/kg bw. At 50 mg/kg bw, 55% of the
dose was detected as urinary metabolites within 23 hr, mainly within the
first 6 h. The amounts of the excreted metabolites expressed as % of
injected dose (250 or 500 mg/kg bw) were lower than that caused by 50
mg/kg bw, and a noticeable amount of the total sums were excreted within
11–23 h, suggesting that the excretion was still continued with the
doses of 250 and 500 mg/kg bw 23 h after injection. The excretion of all
analyzed metabolites was prevented by the pre-treatment of the rats with
1-phenylimidazole, an inhibitor of cytochrome P-450 monooxygenases. This
indicates that these metabolites were formed as catalyzed by cytochrome
P-450. The structures of the analyzed metabolites suggest that the main
reactive intermediate of the test substance is vinyltoluene-7,8-oxide.
Furthermore, the amounts of the excreted metabolites showed that the
main detoxification pathways of vinyltoluene-7,8-oxide were the
conjugation with reduced glutathione and hydration to diols.
Pre-treatment of the rats with PCBs increased the excretion rates of the
metabolites. However, the PCB pre-treated rats excreted less thioethers
(62%) compared to the rats treated only with the same amount of test
substance, whereas the total sum of the other metabolites was about the
same in these both groups. This result suggests that PCBs change the
metabolism of the test substance to some other pathway which could be
glucuronide conjugation because PCBs increased the activity of
UDP-glucuronosyltransferase in a dose-dependent manner (Heinonen, 1984).
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