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Pharmacogenetic variants of the steroid hormone‐metabolizing enzyme cytochrome P450 2B6 (CYP2B6) were reported to be associated with breast cancer (BC) risk and prognosis. CYP2B6 expression is inducible by estradiol (E2) but induction was demonstrated only under steroid hormone‐deprived medium conditions. Physiological conditions, however, even under endocrinological BC treatment, do not correspond to complete steroid hormone depletion. The aim of this study was to investigate the E2‐mediated CYP2B6 and CYP1B1 regulation under various steroid hormone conditions, including physiological concentrations, in human oestrogen receptor positive (T47D, MCF‐7) and negative (MDA‐MB‐231) BC cell lines. We confirm that steroid‐deprived pre‐cultivation led to CYP2B6 upregulation in T47D, but not in MCF‐7. However, when pre‐cultivated with steroid‐containing medium CYP2B6 was downregulated in T47D and MCF‐7, while the addition of physiological E2 concentrations to steroid‐deprived medium resulted in a downregulation in T47D. In contrast, CYP1B1 was never downregulated in any culture condition. Thus, we show that E2‐mediated CYP2B6 regulation in BC cells depends on steroid hormone exposure in a cell line‐specific manner. Our data indicates the importance of being careful with conclusions drawn from CYP2B6 induction findings in vitro, as we demonstrate potential influences of hormonal changes on CYP2B6 expression, which could impact steroid hormone homeostasis and, consequently, BC risk. [ABSTRACT FROM AUTHOR]

CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary‐derived activity marker for CYP2D6. The intraday variability in plasma within individuals has not been studied yet in healthy subjects. As part of a CYP phenotyping cocktail study with 20 healthy participants, plasma concentrations of solanidine, 4‐OH‐solanidine and 3,4‐secosolanidine‐3,4‐dioic acid (SSDA) were determined using a sensitive liquid chromatography‐mass spectrometry method in urine and in plasma at timepoints 0, 2.5, 5, 8, and 24 hours after intake of test substances. The participants were phenotyped for CYP2D6 with oral metoprolol (12.5 mg) with 15 plasma sampling points over 24 hours (DRKS00028922). Metabolic ratios (MRs) of metabolite to parent plasma concentrations were formed from single timepoints and the area under the curve (AUC). All participants were genotyped for CYP2D6. The intra‐individual variability of the CYP2D6 metabolite SSDA was highly stable with a median SD of 11.62% over 24 hours. MR SSDA/solanidine was more variable (median SD 31.90%) but correlated significantly at all measured timepoints with AUC MR α‐OH‐metoprolol/metoprolol. The AUC MR SSDA/solanidine showed a significant linear relationship with the genetically predicted CYP2D6 activity score. This study substantiates the MR SSDA/solanidine as CYP2D6 activity marker. The high correlation with metoprolol MR indicates a valid prediction of the CYP2D6 phenotype at any timepoint during the study day. [ABSTRACT FROM AUTHOR]