title: Metabolism of tauromustine in liver and lung microsomes from various species.
abstract: 1. The cytochrome P450 (CYP)-mediated metabolism of tauromustine has been evaluated in liver and lung microsomes from various species. Liver microsomes from rat pretreated with typical CYP inducers, human liver microsomes and cDNA-expressed human CYP enzymes were used to study the enzymatic basis of the metabolism. The further metabolism of the monodemethylated product of tauromustine and that of the denitrosated product were also investigated. 2. The major routes of tauromustine metabolism were demethylation to the alkylating active compound, R2, and denitrosation to the inactive metabolite, M3. The extent of metabolism and the activity of demethylation versus denitrosation varied among the species. The highest metabolism was found in mouse (BDF strain) followed by dog, rat and the human liver. Tauromustine was also metabolized to a low extent in lung microsomes from these species. 3. The further metabolism of R2 and M3 was approximately 100 times lower in activity than that of tauromustine. Both the demethylation and the denitrosation of tauromustine were increased 3-fold in liver microsomes from rat pretreated with phenobarbital, whereas treatment with cyanopregnenolone enhanced the denitrosation 11-fold, indicating the involvement of CYP3A. 4. Metabolism across a panel of 10 human liver microsomal samples demonstrated a correlation with testosterone 6beta-hydroxylation of demethylation (r2 = 0.86) and denitrosation of tauromustine (r2 = 0.79). Among the human cDNA expressed CYP enzymes, not only was tauromustine determined to be catalysed predominantly by CYP3A4, but also to some extent by CYP2C19 and CYP2D6. 5. In conclusion, the present results indicate a major role of CYP3A enzymes in the metabolism of tauromustine.
authors.affiliation: Pharmacokinetics and Metabolism, Active Biotech Research AB, Lund, Sweden. helen.tuvesson@activebiotech.com
authors.forename: H
authors.initials: H
authors.lastname: Tuvesson
authors.forename: P O
authors.initials: PO
authors.lastname: Gunnarsson
authors.forename: J
authors.initials: J
authors.lastname: Seidegård
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003580:Cytochromes; D004285:Dogs; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009607:Nitrosourea Compounds / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011284:Pregnenolone / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
chemical_list: D003580:Cytochromes; D009607:Nitrosourea Compounds; D013654:Taurine; D013739:Testosterone; C052991:1-(2-chloroethyl)-3-(2-(dimethylaminosulfonyl)ethyl)-1-nitrosourea; D008748:Methylcholanthrene; D011284:Pregnenolone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D039181:Steroid 16-alpha-Hydroxylase; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital