Induction of human cytochrome P450 3A enzymes in cultured placental cells by thalidomide and relevance to bioactivation and toxicity

J Toxicol Sci. 2017;42(3):343-348. doi: 10.2131/jts.42.343.

Abstract

Evidence has been presented for auto-induced human cytochrome P450 3A enzyme involvement in the teratogenicity and clinical outcome of thalidomide due to oxidation to 5-hydroxythalidomide and subsequent metabolic activation in livers. In this study, more relevant human placenta preparations and placental BeWo cells showed low but detectable P450 3A4/5 mRNA expression and drug oxidation activities. Human placental microsomal fractions from three subjects showed detectable midazolam 1´- and 4-hydroxylation and thalidomide 5-hydroxylation activities. Human placental BeWo cells, cultured in the recommended media, also indicated detectable midazolam 1´- and 4-hydroxylation and thalidomide 5-hydroxylation activities. To reduce any masking effects by endogenous hormones used in the recommended media, induction of P450 3A4/5 mRNA and oxidation activities were measured in placental BeWo cells cultured with a modified medium containing 5% charcoal-stripped fetal bovine serum. Thalidomide significantly induced P450 3A4/5, 2B6, and pregnane X receptor (PXR) mRNA levels 2 to 3-fold, but rifampicin only enhanced P450 3A5 and PXR mRNA under the modified media conditions. Under these modified conditions, thalidomide also significantly induced midazolam 1´-hydroxylation and thalidomide 5-hydroxylaion activities 3-fold but not bupropion hydroxylation activity. Taken together, activation of thalidomide to 5-hydroxythalidomide with autoinduction of P450 3A enzymes in human placentas, as well as livers, is suggested in vivo.

Keywords: Drug oxidation; Induction; Phenobarbital; Placenta; Rifampicin.

MeSH terms

  • Cells, Cultured
  • Cytochrome P-450 CYP3A / biosynthesis*
  • Enzyme Induction / drug effects
  • Female
  • Humans
  • Liver / metabolism
  • Oxidation-Reduction
  • Placenta / cytology
  • Placenta / enzymology*
  • Pregnancy
  • Pregnane X Receptor
  • RNA, Messenger / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Rifampin / toxicity
  • Thalidomide / analogs & derivatives
  • Thalidomide / metabolism
  • Thalidomide / toxicity*

Substances

  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Steroid
  • 5-hydroxythalidomide
  • Thalidomide
  • Cytochrome P-450 CYP3A
  • Rifampin