Identification of novel metabolites of the xenoestrogen 4-tert-octylphenol in primary rat hepatocytes.
A number of environmental pollutants, including 4-tert-alkylphenols, can mimic the actions of endogenous steroids and have the potential to disrupt the endocrine function in humans and animals. The biotransformation of a 4-tert-alkylphenol in isolated rat hepatocytes was studied in order to determine the possible fate and activity of these xenoestrogens in higher vertebrates. Hepatocytes were incubated with 30 microM 4-(1',1',3', 3'-tetramethylbutyl)[U-(14)C]phenol (4-tert-octylphenol; t-OP) for up to 60 min. Radiolabelled metabolites were detected by radio-HPLC and the structures determined by gas chromatography-mass spectrometry (GC-MS) analysis of the conjugated or aglycone products. After a 15 min incubation, over 97% of t-OP was metabolised to a complex mixture of metabolites. The initial metabolites formed were identified as products of hydroxylation of the aromatic ring to form catechols and methylated catechols, as well as glucuronide conjugates of the catechol metabolites or parent phenol. These products were further metabolised by hydroxylation of the alkyl chain followed by glucuronide conjugation of the alkoxy group. The conjugated metabolites of t-OP are unlikely to retain estrogen receptor activity, however t-OP is metabolised by some pathways that are similar to that of estrogen catabolism, namely by ortho-hydroxylation to form catechols, methylation by catechol O-methyltransferases and ring conjugation by uridine diphosphoglucuronosyl transferases. Further investigations are needed to determine whether 4-tert-alkylphenols can alter circulating sex steroid profiles by acting as substrates of enzymes determining estrogen metabolism and excretion.
Pedersen
R T
RT
School of Chemistry, Physics and Environmental Science, University of Sussex, Falmer, BN1 9QJ, Brighton, UK.
Hill
E M
EM
D000818:Animals; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D002396:Catechols / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004968:Estrogens, Non-Steroidal / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D020719:Glucuronides / Q000378:metabolism; D006900:Hydroxylation; D008099:Liver / Q000378:metabolism*; D008297:Male; D008745:Methylation; D010636:Phenols / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002396:Catechols; D004968:Estrogens, Non-Steroidal; D020719:Glucuronides; D010636:Phenols; D002394:Catechol O-Methyltransferase; C105260:4-tert-octylphenol