title: Pharmacokinetics and pharmacodynamics of 3,3'-diindolylmethane (DIM) in regulating gene expression of phase II drug metabolizing enzymes.
abstract: 3,3'-Diindolylmethane (DIM) has been investigated as a potential anti-cancer chemopreventive agent in many preclinical and clinical studies. In this study, we sought to characterize the pharmacokinetics of DIM and to build a pharmacokinetic (PK) and pharmacodynamic (PD) model of the DIM-induced gene expression of phase II drug metabolizing enzymes (DME), which potentially links DIM's molecular effects to its in vivo chemopreventive efficacy. DIM (10 mg/kg) was administered intravenously (i.v.) to male Sprague-Dawley rats and blood samples were collected at selected time points for 48 h. The plasma concentration of DIM was determined using a validated HPLC method. The mRNA expression of NQO1, GSTP1 and UGT1A1 in blood lymphocytes was measured using quantitative PCR. An indirect response model was employed to relate the concentration of DIM to the expression of the genes NQO1, GSTP1 and UGT1A1, which were chosen as PD markers for DIM. After i.v. administration, the plasma concentration of DIM declined quickly, and the expression of target genes increased significantly, peaking at 1-2 h and then returning to basal levels after 24 h. The parameters in the PK-PD model were estimated. The PK-PD model aptly described the time delay and magnitude of gene expression induced by DIM. Our results indicate that DIM is effective at inducing various phase II DME, which are capable of detoxify carcinogens. This PK-PD modeling approach provides a framework for evaluating the acute effects of DIM or other similar drugs in clinical trials.
authors.affiliation: Department of Pharmacology, Tzu Chi University, Hualien City, Taiwan.
authors.forename: Tien-Yuan
authors.initials: TY
authors.lastname: Wu
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Chengyue
authors.initials: C
authors.lastname: Zhang
authors.forename: Zheng-Yuan
authors.initials: ZY
authors.lastname: Su
authors.forename: Sarandeep
authors.initials: S
authors.lastname: Boyanapalli
authors.forename: Tin Oo
authors.initials: TO
authors.lastname: Khor
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Hongxia
authors.initials: H
authors.lastname: Lin
authors.forename: Murugesan
authors.initials: M
authors.lastname: Gounder
authors.forename: Leonid
authors.initials: L
authors.lastname: Kagan
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Androulakis
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000235:genetics*; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D050217:Metabolic Detoxication, Phase II; D008954:Models, Biological; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D017207:Rats, Sprague-Dawley; D000099148:UGT1A1 Enzyme
chemical_list: D016588:Anticarcinogenic Agents; D014453:Glucuronosyltransferase; D051549:Glutathione S-Transferase pi; D007211:Indoles; D016660:NAD(P)H Dehydrogenase (Quinone); C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme; C507703:NQO1 protein, rat; C496558:Gstp1 protein, rat; C016392:3,3'-diindolylmethane