A carcinogenicity study of styrene-7,8-oxide in rats

Ponomarkov, V.; Cabral, J. R. P.; Wahrendorf, Jürgen; Galendo, D.

doi:10.1016/0304-3835(84)90085-5

Cited by 38 publications

(10 citation statements)

References 9 publications

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“…While styrene is mutagenic after metablic activation only, styrene oxide is a direct acting mutagen (reviewed in Barale 1991). Styrene oxide has been shown to alkylate proteins and DNA in vitro and in vivo (Marniemi et al 1977;Nordqvist et al 1985) and was carcinogenic after oral administration to rats and mice resulting in forestomach tumors (Maltoni et al 1979;Conti et al 1988;Ponomarkov et al 1984;Lijinsky 1986). Consequently, concern about the carcinogenic potential of styrene itself has been related to the occurrence of styrene oxide as an intermediate metabolite of styrene.…”

Section: Introductionmentioning

confidence: 97%

Species-specific pharmacokinetics of styrene in rat and mouse

Filser¹,

Schwegler²,

Csanády

et al. 1993

Arch Toxicol

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The pharmacokinetics of styrene were investigated in male Sprague-Dawley rats and male B6C3F1 mice using the closed chamber technique. Animals were exposed to styrene vapors of initial concentrations ranging from 550 to 5000 ppm, or received intraperitoneal (i.p.) doses of styrene from 20 to 340 mg/kg or oral (p.o.) doses of styrene in olive oil from 100 to 350 mg/kg. Concentration-time courses of styrene in the chamber atmosphere were monitored and analyzed by a pharmacokinetic two-compartment model. In both species, the rate of metabolism of inhaled styrene was concentration dependent. At steady state it increased linearly with exposure concentration up to about 300 ppm; more than 95% of inhaled styrene was metabolized and only small amounts were exhaled unchanged. At these low concentrations transport to the metabolizing enzymes and not their metabolic capacity was the rate limiting step for metabolism. Pharmacokinetic behaviour of styrene was strongly influenced by physiological parameters such as blood flow and especially the alveolar ventilation rate. At exposure concentrations of styrene above 300 ppm the rate of metabolism at steady state was progressively limited by biochemical parameters of the metabolizing enzymes. Saturation of metabolism (Vmax) was reached at atmospheric concentrations of about 700 ppm in rats and 800 ppm in mice, Vmax being 224 mumol/(h.kg) and 625 mumol/(h.kg), respectively. The atmospheric concentrations at Vmax/2 were 190 ppm in rats and 270 ppm in mice. Styrene accumulates preferentially in the fatty tissue as can be deduced from its partition coefficients in olive oil:air and water:air which have been determined in vitro at 37 degrees C to be 5600 and 15. In rats and mice exposed to styrene vapors below 300 ppm, there was little accumulation since the uptake was rate limiting. The bioaccumulation factor body:air at steady state (K'st*) was rather low in comparison to the thermodynamic partition coefficient body:air (Keq) which was determined to be 420. K'st* increased from 2.7 at 10 ppm to 13 at 310 ppm in the rat and from 5.9 at 20 ppm to 13 at 310 ppm in the mouse. Above 300 ppm, K'st* increased considerably with increasing concentration since metabolism became saturated in both species. At levels above 2000 ppm K'st* reached its maximum of 420 being equivalent to Keq. Pretreatment with diethyldithiocarbamate, administered intraperitoneally (200 mg/kg in rats, 400 mg/kg in mice) 15 min prior to exposure of styrene vapours, resulted in effective inhibition of styrene metabolism, indicating that most of the styrene is metabolized by cytochrome P450-dependent monooxygenases.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Introductionmentioning

confidence: 97%

Species-specific pharmacokinetics of styrene in rat and mouse

Filser¹,

Schwegler²,

Csanády

et al. 1993

Arch Toxicol

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“…Adducts of styrene to proteins and DNA are formed via this metabolic intermediate SO in hemoglobin 4,5) . In mice and rats, it induces tumors dose dependently after oral administration [6][7][8] . This reactive intermediate is, in humans, mainly detoxified by microsomal epoxide hydrolase (EH) to styrene glycol (SG) 9) .…”

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confidence: 99%

Effects of Pregnancy, Age and Sex in the Metabolism of Styrene in Rat Liver in Relation to the Regulation of Cytochrome P450 Enzymes

Kishi¹,

Sata²,

Katakura³

et al. 2005

Journal of Occupational Health

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To elucidate the effect of maternal styrene exposure, which is due to various postnatal changes in the development and behavior of offspring, we investigated pregnancy-induced changes in the metabolism of styrene in rat liver in relation to the regulation of cytochrome P450 enzymes. We also examined age and sex-induced changes in the metabolism of styrene. Pregnancy appeared to exert a negative effect on cytochrome P450 content at the late stage, whereas microsomal protein content showed little change during pregnancy. Pregnancy significantly decreased the rate of formation of styrene glycol at the late stage. The percentage of remaining activity in microsomes exposed to anti-CYP2E1 was lower than that exposed to anti-CYP2C11/6 in pregnant and non-pregnant female rats and immature male rats, indicating that CYP2E1 contributes to the metabolism of styrene more than CYP2C11/6 in these rats. Although pregnancy seemed to decrease styrene metabolism, the contribution of CYP2E1 seemed to be slightly increasing. In conclusion, pregnancy clearly influences the metabolism of styrene as well as other characteristic factors such as age and sex. It is very important to elucidate the changes in specific P450 isozyme composition related to their characteristic modification and in their affinity for chemicals.

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“…© Oxford University Press on the sufficient evidence for the carcinogenicity of styrene-7,8-oxide (SO*), the major intermediate metabolite in vivo: with oral gavage of SO, forestomach tumors were induced in both rats and mice (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Investigation of the covalent binding of styrene-7,8-oxide to DNA in rat and mouse

Cantoreggi

Lutz

1992

Carcinogenesis

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Styrene-7,8-oxide (SO), the main intermediate metabolite of styrene, induces hyperkeratosis and tumors in the forestomach of rats and mice upon chronic administration by gavage. The aim of this study was to investigate whether DNA binding could be responsible for the carcinogenic effect observed. [7?H]SO was administered by oral gavage in corn oil to male CD rats at two dose levels (1.65 or 240 mg/kg). After 4 or 24 h, forestomach, glandular stomach and liver were excised, DNA was isolated and its radioactivity determined. At the 4 h time point, the DNA radioactivity was below the limit of detection in the forestomach and the liver. Expressed in the units of the covalent binding index, CBI = (/unol adduct/mol DNA nucleotide)/(mmol chemical administered/kg body wt), the DNA-binding potency was below 2.6 and 2.0 respectively. In the glandular stomach at 4 h, and in most 24 h samples, DNA was slightly radiolabeled. Enzymatic degradation of the DNA and separation by HPLC of the normal nucleotides showed that the DNA radioactivity represented biosynthetic incorporation of radiolabel into newly synthesized DNA. The limit of detection of DNA adducts in the glandular stomach was 1.0. In a second experiment, [T-TIISO was administered by i.p. injection to male B6C3F1 mice. Liver DNA was analyzed after 2 h. No radioactivity was detectable at a limit of detection of CBI < 0.6. In agreement with the relatively long half-life of SO in animals, the chemical reactivity of SO appears to be too low to result in a detectable production of DNA adducts in an in vivo situation. Upon comparison with the DNA-binding of other carcinogens, a purely genotoxic mechanism of tumorigenic action of SO is unlikely. The observed tumorigenic potency in the forestomach could be the result of strong tumor promotion by high-dose cytotoxkity followed by regenerative hyperplasia.

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A carcinogenicity study of styrene-7,8-oxide in rats

Cited by 38 publications

References 9 publications

Species-specific pharmacokinetics of styrene in rat and mouse

Species-specific pharmacokinetics of styrene in rat and mouse

Effects of Pregnancy, Age and Sex in the Metabolism of Styrene in Rat Liver in Relation to the Regulation of Cytochrome P450 Enzymes

Investigation of the covalent binding of styrene-7,8-oxide to DNA in rat and mouse

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