Sex steroid hormones differentially regulate CYP2D in female wild-type and CYP2D6-humanized mice

Abstract

The CYP2D subfamily catalyses the metabolism of about 25% of prescribed drugs, including the majority of antidepressants and antipsychotics. At present, the mechanism of hepatic CYP2D regulation remains largely unknown. This study investigated the role of sex steroid hormones in CYP2D regulation. For this purpose, Cyp2d22 expression was assessed in the distinct phases of the estrous cycle of normocyclic C57BL/6J (WT) female mice. Cyp2d22 was also evaluated in ovariectomised WT and CYP2D6-humanized (hCYP2D6) mice that received hormonal supplementation with either 17β-estradiol (E2) and/or progesterone. Comparisons were also made to male mice. The data revealed that hepatic Cyp2d22 mRNA, protein and activity levels were higher at estrous compared to the other phases of the estrous cycle and that ovariectomy repressed Cyp2d22 expression in WT mice. Tamoxifen, an anti-estrogenic compound, also repressed hepatic Cyp2d22 via activation of GH/STAT5b and PI3k/AKT signaling pathways. Both hormones prevented the ovariectomy-mediated Cyp2d22 repression. In case of progesterone, this may be mediated by inhibition of the PI3k/AKT/FOX01 pathway. Notably, Cyp2d22 mRNA levels in WT males were similar to those in ovariectomised mice and were markedly lower compared to females at estrous, a differentiation potentially regulated by the GH/STAT5b pathway. Sex steroid hormone-related alterations in Cyp2d22 mRNA expression were highly correlated with Hnf1a mRNA. Interestingly, fluctuations in Cyp2d22 in hippocampus and cerebellum followed those in liver. In contrast to WT mice, ovariectomy induced hepatic CYP2D6 expression in hCYP2D6 mice, whereas E2 and/or progesterone prevented this induction. Apparently, sex steroid hormones display a significant gender- and species-specific role in the regulation of CYP2D.

Oleuropein-Induced Acceleration of Cytochrome P450–Catalyzed Drug Metabolism: Central Role for Nuclear Receptor Peroxisome Proliferator-Activated Receptor α

“…In contrast to the present findings related to the induction of CYP3A14/25 by OLE, previous in vitro studies indicated that OLE and its metabolite hydroxytyrosol, inactivated androstenedione 6beta-hydroxylase (CYP3A4dependent) activity in microsomal preparations of human liver (Stupans et al, 2001;Stupans et al, 2000;Zhou et al, 2007). This discrepancy could be explained primarily, on the basis of a species-specific regulation of the main CYPs (Konstandi et al, 2020;Visioli et al, 2002a) and the different experimental approaches followed in these studies. Current in vivo study evaluated the OLE effect on CYP3A14/25 in mouse liver microsomes, whereas the in vitro studies mentioned above used human liver microsomes (Stupans et al, 2001;Stupans et al, 2000).…”

“…Hnf4a, encoding a nuclear transcription factor, which holds a determinant role in the regulation of several CYP genes (Daskalopoulos et al, 2012a;Konstandi et al, 2020), was also upregulated by OLE in the liver of mice (Malliou et al, 2018), (Supplemental Fig. 1).…”

“…They are usually dependent on the drugs' effect on CYPs acting either as inducers, inhibitors or substrates. On one hand, induction of the most important CYPs that catalyze the metabolism of the majority of prescribed drugs, may accelerate the biotransformation of their drug-substrates and in most cases, result in their reduced pharmacological efficacy (Daskalopoulos et al, 2012a;Daskalopoulos et al, 2012b;Ingelman-Sundberg et al, 2007;Konstandi et al, 2020;Konstandi et al, 2005;Zhou et al, 2004), whereas in some cases, in perturbation of several endogenous regulatory circuits, often associated with pathophysiological states (Choi and Waxman, 1999). On the other hand, inhibition of CYPs may lead to accumulation of their drug-substrates in the blood, followed by adverse side effects of varying severity that may reach the level of toxicity and this is of particular clinical interest when drugs of low therapeutic index are administered (Daskalopoulos et al, 2012b;Konstandi et al, 2020;Spatzenegger and Jaeger, 1995).…”

Antipsychotic medication for women with schizophrenia spectrum disorders

“…The clinical relevance of this sex difference in CYP2D6 activity is probably small (Aichhorn et al, 2005), as individual differences largely depend on highly variable genetic variations in the CYP2D6 gene (Labbé et al, 2000). Sex differences may, therefore, only become apparent when female sex hormones reach significant heights (Gaedigk, Dinh, Jeong, Prasad, & Leeder, 2018; Konstandi, Andriopoulou, Cheng, & Gonzalez, 2020), for example in pregnancy.…”

Stress as a Potential Regulatory Factor in the Outcome of Pharmacotherapy

“…External modifying factors such as stress stimuli, diet, environmental chemicals, toxicants and drugs, as well as infectious diseases can also modify the outcome and toxicity of pharmacotherapy by influencing the pharmacokinetic and pharmacodynamic profile of drugs (Zhou et al, 2009 ; Konstandi et al, 2014 ; Thummel and Lin, 2014 ; Roughead, 2015 ). This is attributed to the fact that they can affect the absorption, distribution, metabolism, elimination and activity of drugs (Zhou et al, 2009 ; Konstandi, 2013 ; Konstandi et al, 2013 , 2014 , 2020 ). In this context, stress plays a central role in the multi-factorial regulation of drugs in the body and in determining a drug's pharmacokinetic profile, as it regulates various enzymes that catalyze the metabolism of the majority of prescribed drugs (Konstandi et al, 2000 , 2004 , 2005 , 2008 , 2014 ; Daskalopoulos et al, 2012 ; Konstandi, 2013 ).…”