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. 2022 Feb 27;14(3):532.
doi: 10.3390/pharmaceutics14030532.

CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity

Ferenc Fekete  1   2 , Katalin Mangó  1 , Annamária Minus  1 , Katalin Tóth  1 , Katalin Monostory  1
Affiliations

CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity

Ferenc Fekete et al. Pharmaceutics. .

Abstract

CYP1A2, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of several drugs and carcinogenic compounds. Data on the significance of CYP1A2 genetic polymorphisms in enzyme activity are highly inconsistent; therefore, the impact of CYP1A2 genetic variants (−3860G>A, −2467delT, −739T>G, −163C>A, 2159G>A) on mRNA expression and phenacetin O-dealkylation selective for CYP1A2 was investigated in human liver tissues and in psychiatric patients belonging to Caucasian populations. CYP1A2*1F, considered to be associated with high CYP1A2 inducibility, is generally identified by the presence of −163C>A polymorphism; however, we demonstrated that −163C>A existed in several haplotypes (CYP1A2*1F, CYP1A2*1L, CYP1A2*1M, CYP1A2*1V, CYP1A2*1W), and consequently, CYP1A2*1F was a much rarer allelic variant (0.4%) than reported in Caucasian populations. Of note, −163C>A polymorphism was found to result in an increase of neither mRNA nor the activity of CYP1A2. Moreover, hepatic CYP1A2 activity was associated with hepatic or leukocyte mRNA expression rather than genetic polymorphisms of CYP1A2. Consideration of non-genetic phenoconverting factors (co-medication with CYP1A2-specific inhibitors/inducers, tobacco smoking and non-specific factors, including amoxicillin+clavulanic acid therapy or chronic alcohol consumption) did not much improve genotype−phenotype estimation. In conclusion, CYP1A2-genotyping is inappropriate for the prediction of CYP1A2 function; however, CYP1A2 mRNA expression in leukocytes can inform about patients’ CYP1A2-metabolizing capacity.

Keywords: CYP1A2; CYP1A2 expression; CYP1A2 genetic polymorphisms; amoxicillin+clavulanic acid; carbamazepine; chronic alcohol consumption; ciprofloxacin; non-genetic factors; phenacetin O-dealkylation activity; smoking.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CYP1A2 activities and expression in liver tissue donors: (a) Frequency distribution of hepatic CYP1A2 activities (phenacetin O-dealkylation); (b) association between CYP1A2 activities and mRNA expression in the liver or (c) mRNA expression in the peripheral leukocytes of human tissue donors. Abbreviations: PM, poor metabolizer; IM, intermediate metabolizer; EM, normal metabolizer. The vertical line between low and high intermediate metabolizers indicates the median activity. In (b) and (c), the boxes display the range; the horizontal lines are for the median, and the whiskers are for the minimum-maximum values. * p < 0.01; ** p < 0.001.
Figure 2
Figure 2
The association between −163C>A SNP (rs762551) in the regulatory region of CYP1A2 gene and (a) hepatic CYP1A2 activity or (b) mRNA expression. The horizontal lines display the median values. Abbreviations: PM, poor metabolizer; IM, intermediate metabolizer; EM, normal metabolizer.
Figure 3
Figure 3
The effect of genetic and non-genetic factors on hepatic CYP1A2 activity (phenacetin O-dealkylation) and CYP1A2 expression in liver tissue donors: (a) The influence of gender and age of the subjects on CYP1A2 activity (<50 years old in blue, >50 years old in orange); (b) the impact of CYP1A2 genetic variations and non-genetic factors (CYP1A2 inhibitor therapy, smoking, amoxicillin+clavulanic acid treatment, chronic alcohol consumption) on CYP1A2 activity and (c) on mRNA expression are presented. The median CYP1A2 activity (dotted line) is for the cutoff value between high and low intermediate metabolizers. Tables provide the number of subjects in various metabolizer groups with the information of relevant non-genetic factors. Abbreviations: PM, poor metabolizer; IM, intermediate metabolizer; EM, normal metabolizer.
Figure 4
Figure 4
The effect of genetic and non-genetic factors on CYP1A2 expression in the leukocytes of patients with psychiatric disorders: The impact of CYP1A2 genetic variations and non-genetic factors (CYP1A2-inducer therapy, smoking) on CYP1A2 expression (a) and the influence of smoking on mRNA expression (b–d) are presented. The horizontal lines display the median values. The table provides the number of subjects in various metabolizer groups with the information of relevant non-genetic factors. Abbreviations: PM, poor metabolizer; IM, intermediate metabolizer; EM, normal metabolizer; * p < 0.05.
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