title: In vitro metabolism and inductive or inhibitive effect of DL111 on rat cytochrome P4501A enzyme.
abstract: In vitro metabolism and the inductive or inhibitive effect of DL111, a non-hormonal early pregnancy-terminating agent, toward cytochrome P450 (CYP) enzymes in rat liver microsomes were studied. In vitro metabolism of DL111 was performed in different rat liver microsomes (pretreated with phenobarbital (PB), dexamethasone (Dex), beta-naphthoflavone (BNF), DL111, respectively) and the catalytic abilities of these microsomes for DL111 were compared with control group. DL111 was well metabolized in microsomes pretreated with beta-naphthoflavone and itself. The K(m) and V(max) was 41.76 +/- 3.26 microM and 15.34 +/- 1.03 nM min(-1) mg(-1) protein for beta-naphthoflavone group, 48.17 +/- 6.06 microM and 17.54 +/- 1.79 nM min(-1)mg(-1) protein for DL111 group, 77.81 +/- 4.73 microM and 3.087 +/- 0.202 nM min(-1)mg(-1) protein for control group, respectively. The rats were pretreated intraperitoneally with the same daily dose of DL111 for different days. The DL111-pretreated microsomal enzymatic activities were evaluated by measuring the metabolic abilities for specific substrates of various enzymes. The results showed that DL111 had the same inductive function as beta-naphthoflavone (the specific inducer of CYP1A) toward rat liver microsomes. The inhibitive effect of DL111 on CYP1A was investigated by coincubating DL111 with the specific substrates of CYP1A-ethoxyresorufin or phenacetin in the microsome induced by beta-naphthoflavone, and the inhibitive level was compared with fluvoxamine (Flu), the specific inhibitor of CYP1A. DL111 inhibited significantly the metabolism of phenacetin and ethoxyresorufin with the inhibition constant (K(i)) 6.836 +/- 0.10 and 1.222 +/- 0.230 microM, respectively and its inhibition potential on CYP1A was higher than fluvoxamine.
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, 353 Yan'an Road, Hangzhou, Zhejiang 310031, PR China.
authors.forename: Yun-Zhen
authors.initials: YZ
authors.lastname: Hu
authors.forename: Tong-Wei
authors.initials: TW
authors.lastname: Yao
mesh_terms: D000020:Abortifacient Agents, Nonsteroidal / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology*; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: D000020:Abortifacient Agents, Nonsteroidal; D004791:Enzyme Inhibitors; D014230:Triazoles; D019324:beta-Naphthoflavone; C030266:3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole; D003907:Dexamethasone; D019363:Cytochrome P-450 CYP1A1; D010634:Phenobarbital