Strain-specific altered nicotine metabolism in 3,3′-diindolylmethane (DIM) exposed mice

A. Joseph Bloom, Pramod Upadhyaya, Evan D. Kharasch

Research output: Contribution to journalArticle

Abstract

Two indole compounds, indole-3-carbinol (I3C) and its acid condensation product, 3,3′-diindolymethane (DIM), have been shown to suppress the expression of flavin-containing monooxygenases (FMO) and to induce some hepatic cytochrome P450s (CYPs) in rats. In liver microsomes prepared from rats fed I3C or DIM, FMO-mediated nicotine N-oxygenation was decreased, whereas CYP-mediated nicotine metabolism to nicotine iminium and subsequently to cotinine was unchanged. Therefore, it was hypothesized that in mice DIM would also suppress nicotine N-oxygenation without affecting CYP-mediated nicotine metabolism. Liver microsomes were produced from male and female C57BL/6 J and CD1 mice fed 2500 parts per million (ppm) DIM for 14 days. In liver microsomes from DIM-fed mice, FMO-mediated nicotine N-oxygenation did not differ from the controls, but CYP-mediated nicotine metabolism was significantly increased, with results varying by sex and strain. To confirm the effects of DIM in vivo, control and DIM-fed CD1 male mice were injected subcutaneously with nicotine, and the plasma concentrations of nicotine, cotinine and nicotine-N-oxide were measured over 30 minutes. The DIM-fed mice showed greater cotinine concentrations compared with the controls 10 minutes following injection. It is concluded that the effects of DIM on nicotine metabolism in vitro and in vivo differ between mice and rats and between mouse strains, and that DIM is an effective inducer of CYP-mediated nicotine metabolism in commonly studied mouse strains.

Original languageEnglish (US)
Pages (from-to)188-194
Number of pages7
JournalBiopharmaceutics and Drug Disposition
Volume40
Issue number5-6
DOIs
StatePublished - Jan 1 2019

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Nicotine
dimethylaniline monooxygenase (N-oxide forming)
Cytochromes
Liver Microsomes
Cotinine
diindolylmethane
Injections
Acids
Liver

Keywords

  • DIM
  • IC3
  • metabolism
  • mouse
  • nicotine

PubMed: MeSH publication types

  • Journal Article

Cite this

Strain-specific altered nicotine metabolism in 3,3′-diindolylmethane (DIM) exposed mice. / Bloom, A. Joseph; Upadhyaya, Pramod; Kharasch, Evan D.

In: Biopharmaceutics and Drug Disposition, Vol. 40, No. 5-6, 01.01.2019, p. 188-194.

Research output: Contribution to journalArticle

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