CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity
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 <i>CYP1A2</i> genetic polymorphisms in enzyme activity are highly inconsistent; therefore, the impact of <i>CYP1A2<...
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MDPI AG
2022-02-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/3/532 |
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| author | Ferenc Fekete Katalin Mangó Annamária Minus Katalin Tóth Katalin Monostory |
| author_facet | Ferenc Fekete Katalin Mangó Annamária Minus Katalin Tóth Katalin Monostory |
| author_sort | Ferenc Fekete |
| collection | DOAJ |
| description | 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 <i>CYP1A2</i> genetic polymorphisms in enzyme activity are highly inconsistent; therefore, the impact of <i>CYP1A2</i> genetic variants (−3860G>A, −2467delT, −739T>G, −163C>A, 2159G>A) on mRNA expression and phenacetin <i>O</i>-dealkylation selective for CYP1A2 was investigated in human liver tissues and in psychiatric patients belonging to Caucasian populations. <i>CYP1A2*1F</i>, 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 (<i>CYP1A2*1F</i>, <i>CYP1A2*1L</i>, <i>CYP1A2*1M</i>, <i>CYP1A2*1V</i>, <i>CYP1A2*1W</i>), and consequently, <i>CYP1A2*1F</i> 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 <i>CYP1A2</i>. 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, <i>CYP1A2</i>-genotyping is inappropriate for the prediction of CYP1A2 function; however, CYP1A2 mRNA expression in leukocytes can inform about patients’ CYP1A2-metabolizing capacity. |
| first_indexed | 2024-03-09T12:59:43Z |
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| id | doaj.art-52ba2d9f6ad841e88aeca70bc3dc8e71 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T12:59:43Z |
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| spelling | doaj.art-52ba2d9f6ad841e88aeca70bc3dc8e712023-11-30T21:56:13ZengMDPI AGPharmaceutics1999-49232022-02-0114353210.3390/pharmaceutics14030532CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 ActivityFerenc Fekete0Katalin Mangó1Annamária Minus2Katalin Tóth3Katalin Monostory4Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok 2, H-1117 Budapest, HungaryInstitute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok 2, H-1117 Budapest, HungaryInstitute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok 2, H-1117 Budapest, HungaryInstitute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok 2, H-1117 Budapest, HungaryInstitute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok 2, H-1117 Budapest, HungaryCYP1A2, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of several drugs and carcinogenic compounds. Data on the significance of <i>CYP1A2</i> genetic polymorphisms in enzyme activity are highly inconsistent; therefore, the impact of <i>CYP1A2</i> genetic variants (−3860G>A, −2467delT, −739T>G, −163C>A, 2159G>A) on mRNA expression and phenacetin <i>O</i>-dealkylation selective for CYP1A2 was investigated in human liver tissues and in psychiatric patients belonging to Caucasian populations. <i>CYP1A2*1F</i>, 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 (<i>CYP1A2*1F</i>, <i>CYP1A2*1L</i>, <i>CYP1A2*1M</i>, <i>CYP1A2*1V</i>, <i>CYP1A2*1W</i>), and consequently, <i>CYP1A2*1F</i> 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 <i>CYP1A2</i>. 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, <i>CYP1A2</i>-genotyping is inappropriate for the prediction of CYP1A2 function; however, CYP1A2 mRNA expression in leukocytes can inform about patients’ CYP1A2-metabolizing capacity.https://www.mdpi.com/1999-4923/14/3/532CYP1A2phenacetin <i>O</i>-dealkylation activityCYP1A2 expression<i>CYP1A2</i> genetic polymorphismsnon-genetic factorssmoking |
| spellingShingle | Ferenc Fekete Katalin Mangó Annamária Minus Katalin Tóth Katalin Monostory CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity Pharmaceutics CYP1A2 phenacetin <i>O</i>-dealkylation activity CYP1A2 expression <i>CYP1A2</i> genetic polymorphisms non-genetic factors smoking |
| title | CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity |
| title_full | CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity |
| title_fullStr | CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity |
| title_full_unstemmed | CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity |
| title_short | CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity |
| title_sort | cyp1a2 mrna expression rather than genetic variants indicate hepatic cyp1a2 activity |
| topic | CYP1A2 phenacetin <i>O</i>-dealkylation activity CYP1A2 expression <i>CYP1A2</i> genetic polymorphisms non-genetic factors smoking |
| url | https://www.mdpi.com/1999-4923/14/3/532 |
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