IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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(c) Metabolism
IARC MONOGRAPHS VOLUME 82
Watabe et al. (1978) clearly demonstrated the NADPH-dependent conversion of
styrene to styrene 7,8-oxide in liver microsomes from male Wistar-King rats, with further
conversion to styrene glycol by epoxide hydrolase.
The role of glutathione conjugation in the metabolism of styrene was recognized by
Seutter-Berlage et al. (1978), who characterized urinary mercapturic acids amounting to
approximately 11% of an intraperitoneal dose of styrene (250 mg/kg bw) in Wistar rats.
The compounds were identified as N-acetyl-S-(1-phenyl-2-hydroxyethyl)cysteine,
N-acetyl-S-(2-phenyl-2-hydroxyethyl)cysteine and N-acetyl-S-(phenacyl)cysteine,
which were present in a 65:34:1 ratio (Seutter-Berlage et al., 1978; Delbressine et al.,
1981). Watabe et al. (1982) administered styrene, racemic styrene 7,8-oxide, R-styrene
7,8-oxide and S-styrene 7,8-oxide (all at 2 mmol/kg bw) to male Wistar rats and found
the two major metabolites mentioned above. For the R-enantiomer, the rate of metabolism
to mercapturic acid was 2.5 times higher than for the S-enantiomer. Nakatsu et al.
(1983) similarly identified these metabolites in the urine of male Sprague-Dawley rats
after intraperitoneal administration of styrene 7,8-oxide (100 mg/kg bw). Truchon et al.
(1990) exposed Sprague-Dawley rats to styrene by inhalation (25–200 ppm
[106–852 mg/m 3 ], 6 h per day, five days per week for four weeks) and found dosedependent
excretion of N-acetyl-S-(1-phenyl-2-hydroxyethyl)cysteine and N-acetyl-
S-(2-phenyl-2-hydroxyethyl)cysteine in urine. Recent attention has focused on stereochemical
aspects of the formation of these mercapturic acids. Coccini et al. (1996)
exposed Sprague-Dawley rats subchronically to styrene (300 ppm [1280 mg/m 3 ], 6 h per
day, five days per week for two weeks). Urine was collected during the last 6 h of
exposure. Approximately 6.5% of the dose was recovered as N-acetyl-R-(1-phenyl-
2-hydroxyethyl)cysteine, 19.5% as N-acetyl-S-(1-phenyl-2-hydroxyethyl)cysteine and
10.3% as N-acetyl-S- or R-(2-phenyl-2-hydroxyethyl)cysteine. Linhart et al. (1998)
dosed Wistar rats intraperitoneally with R-, S- and racemic styrene 7,8-oxide (150 mg/kg
bw) and found that the regioselectivity was similar for all three treatments, yielding a 2:1
mixture of N-acetyl-S-(1-phenyl-2-hydroxyethyl)cysteine and N-acetyl-S-(2-phenyl-
2-hydroxyethyl)cysteine, although the conversion to the mercapturic acids was higher
with R-styrene 7,8-oxide (28% of the dose) than with the S-isomer (19%). In male
B6C3F 1 mice given an intraperitoneal injection of 400 mg/kg bw styrene, the two major
urinary metabolites were N-acetyl-S-(2-hydroxy-2-phenylethyl)cysteine and N-acetyl-
S-(2-hydroxy-1-phenylethyl) cysteine, together comprising 12.5% of the dose (Linhart
et al., 2000).
Several studies have focused on the influence of inducers and inhibitors of xenobiotic
metabolism on the biotransformation of styrene. Treatment of female Wistar rats with
sodium phenobarbital (37.5 mg/kg bw injected intraperitoneally, twice daily for four
days) increased the metabolism of styrene (given by intraperitoneal injection of
455 mg/kg bw on the fifth day), as determined by measurements of urinary metabolites
(Ohtsuji & Ikeda, 1971). Sato and Nakajima (1985) found that treatment of male Wistar