In vitro analysis of factors influencingCYP1A2expression as potential determinants of interindividual variation

Abstract

Individual differences in drug metabolism contribute to interindividual variation that characterizes responses to drugs and risk in exposure to foreign chemicals. Large individual differences are found in expression levels of CYP1A2, a major drug‐metabolizing enzyme. Underlying causes for this variation are not well understood. Several factors, including tobacco smoking, consumption of cruciferous vegetables, and sex, have been associated with modulating CYP1A2 expression. To understand factors regulating expression of CYP1A2 in establishing a causal relationship, this study examined effects of cigarette smoke condensate (CSC), indole‐3‐carbinol (I3C), and 17β‐estradiol (estradiol) on CYP1A2 expression in in vitro systems using human liver and lung cells. Treatment with CSC (2–25 μg/mL) significantly increased levels of CYP1A2 in six cell lines examined, in a concentration‐ and time‐dependent manner. Fold changes in expression levels relative to controls varied among cell lines. CYP1A2 enzymatic activity also increased with CSC exposure. Treatment of H1299 and HepB3 cells with dietary agent I3C (50 and 100 μmol/L) increased CYP1A2 expression. In human cell lines H1299 and H1395, treatment with estradiol (10 and 100 nmol/L) significantly reduced expression of CYP1A2. Using ChIP assays, effects of CSC on histone modifications were analyzed. Increases in H3K4me3 and H4K16ac were observed at several segments in the CYP1A2 gene, whereas H3K27me3 decreased, following CSC treatment. These results suggest that CYP1A2 expression is affected epigenetically by CSC. Additional studies will be needed to further establish regulatory mechanisms underlying effects of various environmental, dietary, and endogenous factors on CYP1A2 expression in better predicting individual variation.

Study of Sex Differences in Duloxetine Efficacy for Depression in Transgenic Mouse Models

“…For instance, duloxetine can be metabolized by cytochrome P450 (CYP) 2D6 and 1A2 (Fric et al, 2008 ) in the liver. Studies found that estrogen might negatively correlated with CYP 2D6 and CYP 1A2 activity (Gex-Fabry et al, 1990 ; Ereshefsky et al, 1991 ; Relling et al, 1992 ; Parkinson et al, 2004 ; Bartkowiak-Wieczorek et al, 2015 ; Xie et al, 2017 ), which might explain that attenuation of endogenous estrogen attenuated the response to duloxetine noted in Ar +/− female mice. In addition, compared to duloxetine-treated female WT, female Thy1-Ar mice showed less elevation of 5-HT and 5-HIAA levels in the HPC (Figure 4B ).…”

Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome

“…Because of hypogonadism and delayed puberty in PWS, females are often prescribed estradiol or estrogen/progesterone combinations found in oral contraceptives, both of which inhibit gene expression and activity of CYP1A2. This inhibition may result in increased drug levels of substrates of CYP1A2 with potential toxicity [ 32 , 63 ].…”

“…Xie at al. reviewed the magnitude of induction effects, with 3.5-fold increase in smokers vs. non-smokers and 25% increase with broccoli containing diets [ 63 ]. The inducibility of CYP1A2 by diet is particularly important to persons with PWS, many of whom follow the Red Yellow Green Diet that contains a high percentage of cruciferous vegetables that are low in calories and high in fiber [ 64 ].…”

Functional Characterization of 21 Rare Allelic CYP1A2 Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin O-Deethylation

“…Considerable inter-individual differences are observed in the in vitro and in vivo enzymatic activity of CYP1A2. These differences become clinically relevant with respect to an individual’s response to CYP1A2-metabolized drugs [ 2 , 14 , 40 , 41 ]. Several studies have also addressed inter-individual variability through associative studies between the clearance of drugs metabolized by CYP1A2 and genetic polymorphisms [ 37 , 42 , 43 , 44 ].…”