Metabolism of the Styrene Metabolite 4-Vinylphenol by Rat and Mouse Liver and Lung

Abstract

Styrene is a widely used chemical in the reinforced plastics industry and in polystyrene production. Its primary metabolic pathway to styrene oxide and then to styrene glycol, which is further metabolized to mandelic acid and phenylglyoxylic acid, has been well studied. However, a few studies have reported finding a minor metabolite, 4-vinylphenol (4-VP), in rat and human urine. The present studies sought to determine if the formation and metabolism of 4-VP in rat and mouse liver and lung preparations could be measured. When styrene was incubated with hepatic and pulmonary microsomal preparations, 4-VP formation could not be measured in these preparations. However, considerable 4-VP metabolizing activity, as determined by the loss of 4-VP, was observed in both mouse and rat liver and lung microsomal preparations. 4-Vinylphenol metabolizing activity in mouse liver microsomes was three times greater than that in rat liver microsomes, and activity in mouse lung microsomes was eight times greater than that in rat lung microsomes. This activity was completely absent in the absence of NADPH. Studies with cytochrome P-450 inhibitors indicated the involvement of CYP2E1 and CYP2F2. Induction of CYP2E1 by pyridine resulted in an increase in 4-VP metabolism by mouse hepatic microsomes but not by pulmonary microsomes. The metabolite(s) formed as a result of this oxidative pathway remain to be identified. In additional studies, glutathione conjugation appeared to be involved in 4-VP metabolism with the highest activity being in mouse lung, with or without the addition of NADPH.

Effects of styrene and its metabolites on different lung compartments of the mouse—cell proliferation and histomorphology

“…4-VP is an intermediate (and hence indicator) of the ring-oxidation pathway and was identiWed as a minor metabolite in the urine of rats (Pantarotto et al, 1978) and exposed workers (PfäZi et al, 1981). In in vitro experiments 4-VP formation by lung and liver microsomes of mice and rats was not conWrmed (Carlson et al, 2001). Considerable 4-VP metabolizing activity, as detected by the loss of 4-VP, was observed by these authors in the preparations, the activity being much higher in mouse than in rat tissues, suggesting that 4-VP may be a short-lived intermediate.…”

4-Vinylphenol-Induced Pneumotoxicity and Hepatotoxicity in Mice

“…They suggested that the 4-VP was formed via the 3,4-oxide and was further metabolized to 4-hydroxystyrene-7,8-glycol . In recent studies we were unable to demonstrate the formation of 4-VP from styrene in rodent microsomal preparations but found that 4-VP was rapidly metabolized by mouse and rat hepatic and pulmonary microsomes involving CYP2E1 and CYP2F2 (7). In a recent study in which rats and mice were exposed by inhalation to [ring-U- 14 C]styrene, Boogaard et al (5) reported nding 14 CO 2 .…”

Scientific Opinion on Flavouring Group Evaluation 22, Revision 1 (FGE.22Rev1): Ring‐substituted phenolic substances from chemical groups 21 and 25

“…Microsomal preparations of mouse liver and lung appeared to be EFSA Journal 2011; 9(5):1990 far more active than microsomes from the same tissues in the rat. In addition, metabolism of 4-vinylphenol in mouse lung microsomes was also observed to occur with glutathione, also in absence of an active cytochrome P450 system (Carlson et al, 2001;Carlson et al, 2002). However, 4-vinylphenol is not a potent GSH-depleting agent in liver and lung tissue in vivo (Turner et al, 2005).…”