IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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IARC MONOGRAPHS VOLUME 82
1–240 μmol/kg bw total mercapturic acids were eliminated, while rats exposed to the
same concentrations eliminated 0.6–67 μmol/kg bw.
Jerina et al. (1970) used rat [strain unspecified] liver microsomes to examine
naphthalene metabolism in vitro and identified naphthalene 1,2-oxide (2, see Figure 1) as
an intermediate in the formation of all major metabolites including glutathione conjugates.
Bock et al. (1976) used hepatocytes from male Sprague-Dawley rats to show that
1,2-dihydro-1,2-dihydroxynaphthalene glucuronide was a major metabolite of
naphthalene.
Usanov et al. (1982) compared the metabolism of naphthalene by microsomal preparations
from rat liver and rabbit lung [strains and sex not specified] by measuring the
formation of 1-naphthol. The metabolic efficiency, i.e. the rate of hydroxylation per nmol
of cytochrome P450, was 7.35 times higher in rabbit lung than in rat liver microsomes.
d’Arcy Doherty et al. (1985) examined the metabolism of 1-naphthol by a reconstituted
cytochrome P450 system from male Wistar rats and identified the products as 1,2and
1,4-naphthoquinones (8 and 14, see Figure 1). Smithgall et al. (1988) examined the
metabolism of trans-1,2-dihydro-1,2-dihydroxynaphthalene (trans-1,2-dihydrodiol) to
the ortho-quinone by cytosolic dihydrodiol dehydrogenase from rat liver, and investigated
the reactivity of the ortho-quinone with the cellular nucleophiles, cysteine and
glutathione. The results showed that ortho-quinones formed by enzymatic oxidation of
dihydrodiols may be effectively scavenged and detoxified by nucleophiles. Buckpitt and
coworkers (Buckpitt & Warren, 1983; Buckpitt et al., 1984, 1985) examined the relationships
among the initial steps in the oxidative metabolism of naphthalene, conjugation
with glutathione and the ability of reactive metabolites of naphthalene to covalently bind
to protein in tissues of male Swiss Webster mice given intraperitoneal doses of
[ 14 C]naphthalene. Binding of naphthalene in lung, liver and kidney was similar in vivo,
but the rate of microsomal metabolic activation of naphthalene was much lower in the
kidney than in liver or lung. Phenobarbital pretreatment increased the binding in all three
tissues but only at the highest dose (400 mg/kg bw). 1-Naphthol was shown not to be an
obligate intermediate in the binding process. The metabolism of naphthalene by mouse,
rat and hamster pulmonary, hepatic and renal microsomal preparations was compared by
Buckpitt et al. (1987). In all cases, glutathione adducts derived from naphthalene
1,2-oxide were formed and overall activity was particularly high in mouse lung, with a
particular preference in this tissue for the formation of the naphthalene 1R,2S-oxide
isomer (10:1 ratio with the 1S,2R-isomer).
Lanza et al. (1999) examined the ability of microsomal fractions from human
lymphoblastoid cells expressing recombinant human CYP2F1 enzyme to metabolize
naphthalene to glutathione adducts. The predominant conjugates formed were derived
from naphthalene 1S,2R-oxide (see Table 8), in contrast to the findings in mice (Buckpitt
et al., 1992) (see Figure 2).
In view of the mouse lung as a target tissue, a number of investigators have examined
species, tissue and cytochrome P450 (CYP) isozyme specificities in naphthalene metabolism.
Nagata et al. (1990) identified the principal pulmonary enzyme in the mouse as