In vitro metabolism of tributyltin and triphenyltin by human cytochrome P-450 isoforms.
The metabolic fate of tributyltin and triphenyltin may contribute to the toxicity of these chemicals. We used human hepatic cytochrome P-450 (CYP) systems to confirm the specific CYP(s) involved in the in vitro metabolism of tributyltin and triphenyltin. There were no significant sex differences in the metabolic pattern of tributyltin or triphenyltin, indicating that the CYP(s) responsible for the metabolism of these chemicals in humans is/are not sex-specific form(s). Six major drug-metabolizing isoforms of cDNA-expressed human CYPs and the CYP2C subfamily were tested to determine their metabolic capacities for tributyltin and triphenyltin. CYP2C9, 2C18, 2C19, and 3A4 significantly mediated both dealkylation and dearylation of these triorganotins. Furthermore, the metabolism of tributyltin and triphenyltin was significantly inhibited in vitro by pretreatment with selective inhibitors, azamulin for CYP3A4 and N-3-benzylnirvanol for CYP2C19. Since the CYP2C18 content of hepatic microsomes in humans is relatively low, CYP2C9, 2C19, and 3A4 might be the main isoforms of CYP that are responsible for tributyltin and triphenyltin metabolism in the human liver.
Ohhira
Shuji
S
Department of Hygiene, Dokkyo Medical University School of Medicine, Mibu-Machi, Tochigi 321-0293, Japan. s-ohhira@dokkyomed.ac.jp <s-ohhira@dokkyomed.ac.jp>
Enomoto
Mitsunori
M
Matsui
Hisao
H
D001711:Biotransformation; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008617:Mephenytoin / Q000031:analogs & derivatives / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D009947:Organotin Compounds / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
D001952:Bridged-Ring Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C454675:N-3-benzylnirvanol; D009947:Organotin Compounds; D011994:Recombinant Proteins; D014220:Trialkyltin Compounds; D014230:Triazoles; C011559:tributyltin; C489644:azamulin; D003577:Cytochrome P-450 Enzyme System; C030665:triphenyltin; D008617:Mephenytoin