Glucuronidation of nonylphenol and octylphenol eliminates their ability to activate transcription via the estrogen receptor.
Both p-nonylphenol (NP) and p-octylphenol (OP) exhibit weak estrogen-like activity in in vitro and in some rodent assays. To help understand the biochemical and molecular basis for these effects, and thus to permit extrapolation of risk to human health, it is important to establish whether these activities are retained by their metabolites. These data are particularly important in light of the knowledge that both NP and OP are rapidly and extensively metabolized to their glucuronide conjugates in rats. The activity of these glucuronide metabolites, however, is unknown. These studies investigated the intrinsic ability of NP, OP, and their principal mammalian metabolites, nonylphenol glucuronide (NPG) and octylphenol glucuronide (OPG), to affect estrogen receptor (ER)- or androgen receptor (AR)-mediated transcription in a yeast transcriptional activation system. Specifically, the estrogen-, anti-estrogen-, androgen-, and anti-androgen-like activities of NP, OP, NPG, and OPG have been assessed using recombinant yeast strains that express either human ER or AR. The two parent compounds, NP (EC(50) 110 nM) and OP (EC(50) 700 nM), exhibited intrinsic estrogen-like activity in this system, and consistent with numerous studies with these chemicals, they were 3-4 orders of magnitude less potent than 17beta-estradiol (EC(50) 500 pM). However, in contrast to the parent molecules, neither NPG nor OPG exhibited any evidence of estrogen-, antiestrogen-, androgen-, or anti-androgen-like activity in these recombinant yeast strains. Therefore, the weak estrogen-like activity noted for NP and OP in vivo at high doses is likely to reflect saturation of parent molecule glucuronidation. At anticipated levels of human exposure to NP and OP such a saturation of detoxification is highly unlikely; therefore, these in vitro data support the conclusion that the potential endocrine hazard posed by NP and OP to humans is likely to be negligible.
Moffat
G J
GJ
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, United Kingdom.
Burns
A
A
Van Miller
J
J
Joiner
R
R
Ashby
J
J
D000726:Androgen Antagonists / Q000494:pharmacology; D003470:Culture Media; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D020719:Glucuronides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D000726:Androgen Antagonists; D003470:Culture Media; D004965:Estrogen Antagonists; D020719:Glucuronides; D010636:Phenols; D011960:Receptors, Estrogen; D013196:Dihydrotestosterone; D004958:Estradiol; C025256:nonylphenol; C080417:4-octylphenol