The induction of hepatic microsomal UDP-glucuronosyltransferase by the methylsulfonyl metabolites of polychlorinated biphenyl congeners in rats
Introduction
Polychlorinated biphenyls (PCBs) are environmental pollutants that accumulate in the food chain due to their high lipophilicity and low biotransformation rate [1], [2]. Their bioaccumulation has been detected in the environment [3], [4] and in human adipose tissue and milk [5], [6].
A number of the methylsulfonyl (MeSO2) metabolites of PCBs have been found in several species of animals in Canada and Sweden [7], [8], [9], [10] and in healthy humans, as well as in Yusho patients in Japan [11], [12]. Recently, MeSO2-PCBs were identified in Swedish human milk [13], in human blood, liver and adipose tissue [14], [15]. The main MeSO2-PCBs in human milk and tissues of humans and mammals have been shown to be 3- and 4-MeSO2 derivatives of PCBs with chlorine atoms in the 2,5- or 2,5,6-position [7], [8], [9], [10], [13], [14], [15]. The biological activities and toxicological significance of MeSO2 metabolites have not been clarified.
In our papers [16], [17], [18], we reported that the nine 3-MeSO2 metabolites of PCBs were the potent inducers of hepatic microsomal drug-metabolizing enzymes, CYP2B1 and CYP2B2 at levels several hundred-fold lower than required for equivalent induction by parent PCBs [17], [18], while their isomeric 4-MeSO2 metabolites were not. We also showed that the 3-MeSO2 metabolites derived from 2,2′,4,5,5′-pentachlorobiphenyl (2,2′,4,5,5′-pentaCB, CB101) contributed to the induction of the enzymes by the parent compounds [19]. Recently we showed that the seven 3-MeSO2 and two 4-MeSO2 metabolites of tetra-, penta- and hexaCBs reduced serum thyroxine (T4) level and increased serum thyroid stimulating hormone level in rats [20], [21], [22].
A number of compounds known to induce hepatic microsomal drug-metabolizing enzymes in rat liver have been found to induce also UDP-glucuronosyltransferase (UDP-GT), a typical enzyme to catalyze phase II reactions [23], [24]. In the present study, therefore, we investigated the effects of 3- and 4-MeSO2 metabolites of nine PCB congeners on the activity of UDP-GT and the correlation between the induction of UDP-GT and the alterations of thyroid hormone levels. These metabolites are major MeSO2 metabolites accumulated in human liver and adipose tissue and the tissues of several mammalian species [7], [8], [9], [10], [14]. Fig. 1 shows the chemical structures of MeSO2 derivatives of PCB congeners used in this study.
Section snippets
Chemicals
The MeSO2-PCBs were prepared as described elsewhere [25]. The purity of these compounds was >99% when analyzed by gas chromatography. Panacete 810 (medium-chain triglycerides) was purchased from Nippon Oils and Fats Co. Ltd (Tokyo, Japan). All other chemicals, with appropriate purity, were commercially obtained.
Animal treatments
Male Sprague–Dawley rats, weighing 180–200 g (Charles River Japan), were housed three or four per cage in the laboratory with free access to commercial chow and tap water, and maintained
Changes in hepatic microsomal UDP-GT activities after the administration of 3- and 4-MeSO2 metabolites of PCB congeners
Fig. 2 shows the effects of nine MeSO2 derivatives (four consecutive daily doses of 20 μmol/kg) on the activities of UDP-GTs in the liver microsomes of rats. Three substrates (chloramphenicol, 4-nitrophenol and 4-methylumbelliferone) were used to examine whether induction to UDP-GTs had occurred. Mackenzie’s et al. [31] nomenclature was used to designate UDP-GT. The activity of UDP-GT toward chloramphenicol (UGT2B1; phenobarbital-inducible UGT) increased after the administration of the seven
Discussion
Two UDP-GT isozymes, 3-methylcholanthrene-inducible UDP-GT (using 4-nitrophenol or 4-methylumbelliferone as substrate) and phenobarbital-inducible UGT (using chloramphenicol as substrate) are named UGT1A6 and UGT2B1, respectively [31]. Seven 3-MeSO2-PCBs and 4-MeSO2-CB101 (20 μmol/kg once daily for 4 days) induced two forms of UDP-GT with activities toward chloramphenicol, 4-nitrophenol and 4-methylumbelliferone, whereas 4-MeSO2-CB149 induced a form of UDP-GT with activity toward
Acknowledgements
We acknowledge Yuka Tachino for her technical assistance. The work was partially funded by a Grant-in-Aid for Scientific Research (C) (no. 09680531) from the Ministry of Education, Science, Sports and Culture of Japan, grants from the Showa Shell Sekiyu Foundation for Promotion of Environmental Research and Health Sciences Research Grants from the Ministry of Health and Welfare.
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