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EC number: 946-365-8
CAS number: -
data is being read across from the source study that tested
1-methylnaphthalene based on analogue read across.
The first step in the metabolism of
methylnaphthalenes can occur either via ring epoxidation or via
oxidation of the methyl side chain to generate an alcohol. Both
processes are catalyzed by the cytochrome P450 monooxygenases.
Investigators showed that the most catalytically active proteins
involved in naphthalene metabolism (as assessed by Vmax/Km) were CYP1A2
and CYP2E1. CYP1A2 is localized primarily in the liver whereas CYP2E1 is
found in a number of organs including respiratory tissue. More recent
investigations have shown that CYP2A13 metabolizes naphthalene with
relatively high turnover and low Km. Since this protein is expressed in
human lung, albeit with a high degree of variability, it is a potential
candidate for catalyzing the initial metabolism of naphthalene in human
Other data available come from work
conducted with a single recombinant protein, CYP2F2. Although this
protein appears to be abundant in airways of the mouse, available
evidence suggests that the rat and Rhesus macaque orthologues are
present in far smaller amounts in the lung. This protein metabolizes
naphthalene, 2-methylnaphthalene and 1-nitronaphthalene, all with
relatively low Km and high Vmax, and, based on inhibition studies with
5-phenyl-1-pentyne, appears to play a major role in the epoxidation of
closely related substrates, i.e. styrene. These data suggest that this
protein plays a quantitatively important role in the metabolic
activation of these substrates at least in the mouse. The presence of
large quantities of this protein in target cells may explain the species
differences in susceptibility to naphthalene and 2-methylnaphthalene in
mouse but not in rat.
Urinary Metabolites. The most prominent
metabolites isolated in rat urine after treatment with low doses of
2-methylnaphthalene originated from initial oxidation of the parent
hydrocarbon on the methyl moiety. Thirty to thirty-five percent of a
dose of 14C-2-methylnaphthalene was recovered as a glycine conjugate of
2-naphthoic acid. Six to eight percent of the dose was represented by
dihydrodiols and 3-5% of the dose was recovered as parent hydrocarbon.
Other polar metabolites appeared to account for 35-45% of the
radioactivity in the urine. Later work, showed that approximately 75% of
the radioactive metabolites eliminated in the urine of guinea pigs
administered a low dose of 3H-2-methylnaphthalene resulted from
oxidation of the methyl group. These metabolites included free naphthoic
acid, the glucuronide of naphthoic acid as well as the glycine
conjugate. In these studies, a cysteine derivative, accounting for
approximately 10% of the total urinary radioactivity, was reported in
the urine. Finally, small percentages of sulfate and glucuronide
conjugates of 8-hydroxy-2-methylnaphthalene (<10% of total urinary
radioactivity) were measured.
More recent studies on the disposition and
metabolism of 3H-1,2-dimethylnaphthalene (28 mg/kg) in rats showed that
the radioactive parent compound was rapidly absorbed after ip
administration, reaching peak levels within 4 h. Sixty-five percent of
the administered radioactivity was recovered in the excreta within 24 h,
with roughly equal amounts eliminated in the urine and feces. Greater
than 95% of the administered radioactivity was recovered in the excreta
within 72 h of administration. The highest tissue concentrations of
radioactivity were observed in fat, but these fell rapidly to very low
levels within 48 h. This compound apparently distributes rapidly to the
fat but redistributes easily due to the rapid clearance of the compound.
Urinary metabolites were identified in ether extracts of acidified (pH
1) urine. The parent compound (representing roughly 30% of the
ether-extractable metabolites from urine), several
dimethylthionaphthols, at least 2 dimethylmethylthionaphthalene
derivatives as well as several derivatives generated from oxidation of
the methyl groups to the alcohol and subsequently to the acid were
measured in the urine following dimethylnaphthalene administration. The
most prominent metabolites were the dimethylthionaphthol derivatives and
the metabolites generated from side chain oxidation. It is noted that
the 30% of the radioactivity unextracted by ether at pH 1may include a
number of conjugated metabolites including glucuronides, sulfates and
mercapturic acids. The results from more recent studies of the
metabolism and distribution of radioactivity from
3H-1,4-dimethylnaphthalene and 1,6-dimethylnaphthalene are nearly
identical to those with the 1,2-dimethylnaphthalene derivative. Again,
radioactivity is rapidly absorbed reaching peak plasma concentrations
within 4 h of administration. Metabolites which were derived from both
oxidation of the methyl groups and the aromatic nucleus were isolated
from the urine of treated rats.
These metabolites included methylnaphthoic
acid as well as the intermediates leading to this derivative
(methylhydroxymethyl, methylnaphthaldehyde). Trace quantities of a
methylthio metabolite were observed; these metabolites have been
measured in the urine of naphthalene-treated rodents as well.
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