Benzo[a]pyrene toxicokinetics in humans following dietary supplementation with 3,3′-diindolylmethane (DIM) or Brussels sprouts

• Published in: Toxicology and applied pharmacology Vol. 460; no. C; p. 116377
• Main Authors: Vermillion Maier, Monica L., Siddens, Lisbeth K., Pennington, Jamie M., Uesugi, Sandra L., Tilton, Susan C., Vertel, Emily A., Anderson, Kim A., Tidwell, Lane G., Ognibene, Ted J., Turteltaub, Kenneth W., Smith, Jordan N., Williams, David E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2023; Elsevier
• Subjects: 3,3’-diindolylmethane; Accelerator mass spectrometry; Benzo(a)pyrene; Brussels sprouts; Carcinogens; Dietary Supplements; Human carcinogen dosing; Humans; Toxicokinetics; BaP-7,8-DHD; FDA IND; DBC; CHL; PBPK; Accelerator mass spectrometry; RPF; AFB1; AHR; NPL; N2-dG; AUC; BaP; BR-DIM; Brussels sprouts; US EPA; Benzo[a]pyrene; PhIP; CYP; LLNL; BMI; LOD; Cmax; BaP-DHDE; AMS; IQ; DIM; HCC; IARC; PBMC; LOQ; Toxicokinetics; OSU; MeIQx; ATSDR; IPCS; UPLC; PAH; Tmax; IRB; JEFCA; Human carcinogen dosing; 3,3’-diindolylmethane
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2023.116377

Utilizing the atto-zeptomole sensitivity of UPLC-accelerator mass spectrometry (UPLC-AMS), we previously demonstrated significant first-pass metabolism following escalating (25–250 ng) oral micro-dosing in humans of [14C]-benzo[a]pyrene ([14C]-BaP). The present study examines the potential for supplementation with Brussels sprouts (BS) or 3,3′-diindolylmethane (DIM) to alter plasma levels of [14C]-BaP and metabolites over a 48-h period following micro-dosing with 50 ng (5.4 nCi) [14C]-BaP. Volunteers were dosed with [14C]-BaP following fourteen days on a cruciferous vegetable restricted diet, or the same diet supplemented for seven days with 50 g of BS or 300 mg of BR-DIM® prior to dosing. BS or DIM reduced total [14C] recovered from plasma by 56–67% relative to non-intervention. Dietary supplementation with DIM markedly increased Tmax and reduced Cmax for [14C]-BaP indicative of slower absorption. Both dietary treatments significantly reduced Cmax values of four downstream BaP metabolites, consistent with delaying BaP absorption. Dietary treatments also appeared to reduce the T1/2 and the plasma AUC(0,∞) for Unknown Metabolite C, indicating some effect in accelerating clearance of this metabolite. Toxicokinetic constants for other metabolites followed the pattern for [14C]-BaP (metabolite profiles remained relatively consistent) and non-compartmental analysis did not indicate other significant alterations. Significant amounts of metabolites in plasma were at the bay region of [14C]-BaP irrespective of treatment. Although the number of subjects and large interindividual variation are limitations of this study, it represents the first human trial showing dietary intervention altering toxicokinetics of a defined dose of a known human carcinogen. [Display omitted] •[14C]-Benzo[a]pyrene (BaP) toxicokinetics (TK) were studied in humans with UPLC-AMS.•The rate but not extent of BaP absorption was reduced by Brussels sprouts and DIM.•Intervention reduced total [14C] recovered from plasma by 56–67%.•TK constants such as clearance and the metabolic profile of BaP were unchanged.•Impacts on TK are due to gut absorption of BaP, not alteration of metabolism.