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

• Published in: Journal of toxicological sciences Vol. 42; no. 3; pp. 343 - 348
• Main Authors: Arata, Kazuya, Kazuki, Yasuhiro, Guengerich, F. Peter, Murayama, Norie, Harada, Tasuku, Yamazaki, Hiroshi, Satoh, Daisuke, Shibata, Norio
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 2017; Japan Science and Technology Agency
• Subjects: Activation analysis; Biocompatibility; Biomedical materials; Bupropion; Cells, Cultured; Charcoal; Cytochrome; Cytochrome P-450 CYP3A - biosynthesis; Cytochrome P450; Drug oxidation; Enzyme Induction - drug effects; Enzymes; Female; Gene expression; Hormones; Humans; Hydroxylation; Induction; Liver - metabolism; Masking; Media; Metabolic activation; Metabolic rate; Midazolam; Oxidation; Oxidation-Reduction; Phenobarbital; Placenta; Placenta - cytology; Placenta - enzymology; Pregnancy; Pregnane X Receptor; Receptors, Steroid - genetics; Receptors, Steroid - metabolism; Rifampicin; Rifampin; Rifampin - toxicity; RNA, Messenger - metabolism; Surgical implants; Teratogenicity; Thalidomide; Thalidomide - analogs & derivatives; Thalidomide - metabolism; Thalidomide - toxicity; Toxicity; Phenobarbital; Placenta; Rifampicin; Induction; Drug oxidation
• ISSN: 0388-1350; 1880-3989; 1880-3989
• DOI: 10.2131/jts.42.343

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.