Abstract
3,3'-Diindolylmethane (DIM), a major phytochemical derived from ingestion of cruciferous vegetables, is also a dietary supplement. In preclinical models, DIM is an effective cancer chemopreventive agent and has been studied in a number of clinical trials. Previous pharmacokinetic studies in preclinical and clinical models have not reported DIM metabolites in plasma or urine following oral dosing and the pharmacological actions of DIM on target tissues is assumed to be solely via the parent compound. Seven subjects (6 males and 1 female) ranging from 26-65 years of age, on a cruciferous vegetable-restricted diet prior to and during the study, took 2 BioResponse-DIM ® 150 mg capsules (45.3 mg DIM/capsule) every evening for one week with a final dose the morning of the first blood draw. A complete time course was performed with plasma and urine collected over 48 hours and analyzed by UPLC-MS/MS. In addition to parent DIM, two mono-hydroxylated metabolites and 1 di-hydroxylated metabolite, along with their sulfate and glucuronide conjugates, were present in both plasma and urine. Results reported here are indicative of significant phase 1 and phase 2 metabolism and differ from previous pharmacokinetic studies in rodents and humans which reported only parent DIM present following oral administration. 2-Ox-DIM, identified as one of the mono-hydroxylated products, exhibited greater potency and efficacy as an AHR agonist when tested in an XRE-luciferase reporter assay using Hepa1 cells. In addition to competitive phytochemical-drug adverse reactions, additional metabolites may exhibit pharmacological activity highlighting the importance of further characterization of DIM metabolism in humans. Significance Statement 3,3'-Diindolylmethane (DIM), derived from indole-3-carbinol in cruciferous vegetables, is an effective cancer chemopreventive agent in pre-clinical models and a popular dietary supplement currently in clinical trials. Pharmacokinetic studies to date found little or no metabolites in plasma or urine. In marked contrast, we demonstrate rapid appearance of mono- and di-hydroxylated metabolites in human plasma and urine as well as sulfate and glucuronide conjugates. 2-Ox-DIM exhibited significant AHR agonist activity emphasizing the need for characterization of pharmacological properties of DIM metabolites.
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