Covalent binding of styrene to DNA in rat and mouse

Abstract

Covalent binding of ^-^styrene (S) to DNA in vivo was measured and evaluated in a quantitative manner in order to investigate whether DNA adduct formation could form a mechanistic basis for tumor induction in a carcinogenicity bioassay. [7-3 H]S was administered by inhalation in a closed chamber to male and female CD rats and B6C3F1 mice. After 4.5-6 h (rats) and 6-9 h (pools of four mice), S doses of 23-39 and 85-110 mg/kg respectively had been metabolized. DNA was purified to constant specific radioactivity which was measurable in all samples. DNA was enzymatically degraded to the 3'-nucleotides which were separated by HPLC for the detection of radiolabeled nucleotide-S adducts. The fractions with the normal nucleotides contained most of the radioactivity. In mouse liver DNA, a minute but significant level of adduct radioactivity was also detected. It is concluded that the DNA-binding potency of S is so low that significant tumor induction in a standard bioassay for carcinogenicity is unlikely to be due to DNA adduct formation alone. Consequences for a human risk estimation are discussed.

Styrene Respiratory Tract Toxicity and Mouse Lung Tumors Are Mediated by CYP2F-Generated Metabolites

“…The covalent binding index (CBI) as defined by Lutz (1979) was found to be similar for both species and organs: approximately 0.3 in liver and lung of rats and mice; at 42 h CBI values in liver were 0.14 and 0.44 for rats and mice, respectively. These values confirm the earlier estimates made by Cantoreggi and Lutz (1993) that styrene (and its metabolites) reactions with DNA in vivo are very limited.…”

Comparison of DNA‐Reactive Metabolites from Nitrosamine and Styrene Using Voltammetric DNA/Microsomes Sensors

“…Styrene is metabolized to styrene oxide, which forms up to 11 covalent adducts with guanine and adenine bases of DNA that disrupt the double helix [29 – 31]. Pathways of DNA adduct formation by bioactivation of NPYR and styrene are illustrated in Scheme 2, and were confirmed in this work by LC-MS using polyion/microsomes nanoreactors.…”

Simultaneous Direct Electrochemiluminescence and Catalytic Voltammetry Detection of DNA in Ultrathin Films

“…Reaction of Nucleic Acid Films with Styrene Oxide . The purine bases guanine and adenine in DNA form covalent adducts with styrene oxide, with the majority of reactions occurring at guanine. − Such adducts can serve as important markers of human exposure to mutagens and carcinogens. , Further, covalent adduct formation disrupts the double helical structure of DNA and makes the guanines more accessible for catalytic oxidation, even when the DNA is present in polyion films , …”