The role of sulfation in the metabolic activation of N-hydroxy-4'-fluoro-4-acetylaminobiphenyl.
The role of sulfation in the metabolic activation of the liver carcinogen N-hydroxy-4'-fluoro-4-acetylaminobiphenyl (N-OH-FAABP) in male rat liver was investigated. N-OH-FAABP was a substrate for sulfotransferases in vitro and sulfation was inhibited by the sulfotransferase inhibitors pentachlorophenol (PCP) and 2,6-dichloro-4-nitrophenol (DCNP). The main metabolite of N-OH-FAABP excreted in bile in vivo, and in the isolated perfused liver, was identified as the N-O-glucuronide conjugate. Inhibition of sulfation in vivo by PCP or DCNP, or in vitro by omission of inorganic sulfate, resulted in a large increase in the excretion of the N-O-glucuronide conjugate. It was estimated that at least 21% of the dose was sulfated in control animals. Inhibition of sulfation in vivo by PCP or DCNP prevented the covalent binding of N-OH-FAABP to liver (and kidney) macromolecules by 70% and 20% respectively. HPLC analysis of the fluorobiphenyl DNA and RNA adducts showed that the formation of both N-acetylated and deacetylated (deoxy)-guanosine adducts was prevented. Furthermore, omission of inorganic sulfate in the isolated perfused liver prevented the formation of all fluorobiphenyl DNA adducts by 70-80%. It is concluded that two sulfotransferase-dependent pathways exist for the metabolic activation of N-OH-FAABP in male rat liver: (i) direct sulfation of the hydroxamic acid, resulting, upon decomposition of the FAABP-N-sulfate ester, in the formation of N-acetylated DNA adducts and (ii) deacetylation followed by sulfation of the hydroxylamine to FABP-N-sulfate, leading to the formation of deacetylation DNA adducts.
van de Poll
M L
ML
Division of Toxicology, University of Leiden, The Netherlands.
Tijdens
R B
RB
Vondrácek
P
P
Bruins
A P
AP
Meijer
D K
DK
Meerman
J H
JH
D000611:Aminobiphenyl Compounds / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002733:Chlorophenols / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology*; D010416:Pentachlorophenol / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism*; D013466:Sulfurtransferases / Q000037:antagonists & inhibitors*
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D002733:Chlorophenols; D009596:Nitrophenols; D013431:Sulfates; C015802:2,6-dichloro-4-nitrophenol; D012313:RNA; C017373:N-hydroxy-4-acetylamino-4'-fluorobiphenyl; D004247:DNA; D010416:Pentachlorophenol; D013466:Sulfurtransferases; D005966:Glucuronidase