Metabolism and Mechanism of Human Cytochrome P450 Enzyme 1A2

Abstract

Human cytochrome P450 enzyme 1A2 (CYP1A2) is one of the most important cytochrome P450 (CYP) enzymes in the liver, accounting for 13% to 15% of hepatic CYP enzymes. CYP1A2 metabolises many clinical drugs, such as phenacetin, caffeine, clozapine, tacrine, propranolol, and mexiletine. CYP1A2 also metabolises certain precarcinogens such as aflatoxins, mycotoxins, nitrosamines, and endogenous substances such as steroids. The regulation of CYP1A2 is influenced by many factors. The transcription of CYP1A2 involves not only the aromatic hydrocarbon receptor pathway, but also many additional transcription factors, and CYP1A2 expression may be affected by transcription coactivators and compression factors. Degradation of CYP1A2 mRNA and protein, alternative splicing, RNA stability, regulatory microRNAs, and DNA methylation are also known to affect the regulation of CYP1A2. Many factors can lead to changes in the activity of CYP1A2. Smoking, polycyclic aromatic hydrocarbon ingestion, and certain drugs (e.g., omeprazole) increase its activity, while many clinical drugs such as theophylline, fluvoxamine, quinolone antibiotics, verapamil, cimetidine, and oral contraceptives can inhibit CYP1A2 activity. Here, we review the drugs metabolised by CYP1A2, the metabolic mechanism of CYP1A2, and various factors that influence CYP1A2 metabolism. The metabolic mechanism of CYP1A2 is of great significance in the development of personalised medicine and CYP1A2 target-based drugs.

Evaluation of CYP1A2 activity: Relationship between the endogenous urinary 6‐hydroxymelatonin to melatonin ratio and paraxanthine to caffeine ratio in dried blood spots

“…However, it seems essential to assess whether the 6‐hydroxymelatonin/melatonin ratio is still able to capture the impact of factors contributing significantly to CYP1A2 modulation, despite slightly higher intra‐ and interindividual variability than the paraxanthine/caffeine ratio. In particular, the impact of gender, genetics, pathological states (e.g., liver disease), or comedication on the urinary 6‐hydroxymelatonin/melatonin ratio should be further investigated in future projects, taking into account the variability measured in this study to estimate the sample size 1,47–49 . In particular, smoking, a potent inducer of CYP1A2 enzyme activity, is expected to increase any metabolite‐to‐substrate ratio.…”

“…Cytochrome P450 1A2 (CYP1A2) is one the most important CYP enzymes in the human liver 1 . Its expression has been reported to vary from 40‐ to 130‐fold in the human population 2 .…”

“…Its expression has been reported to vary from 40‐ to 130‐fold in the human population 2 . The causes of variability in CYP1A2 activity are numerous and primarily include non‐genetic factors, such as smoking, drug–drug interactions, age, or gender 1 . Globally, clinical impact of CYP1A2 genotyping is prone to conflicting evidence in the literature, and phenotype prediction from CYP1A2 genotype is not well‐established 3–5 .…”

“…Cytochrome P450 1A2 (CYP1A2) is one the most important CYP enzymes in the human liver. 1 Its expression has been reported to vary from 40‐ to 130‐fold in the human population. 2 The causes of variability in CYP1A2 activity are numerous and primarily include non‐genetic factors, such as smoking, drug–drug interactions, age, or gender.…”

The Roles of microRNAs in Cancer Multidrug Resistance

“…CYP1A2 is one of the most important enzymes involved in drug metabolism; its expression in the liver reaches 13–15% of all CYPs [ 106 ], and it is metabolized by approximately 9% of currently prescribed drugs [ 107 ]. Several polymorphisms of the CYP1A2 gene are associated with an increase in its drug-metabolizing activity and a worsening of the prognosis of, for example, lung cancer [ 108 , 109 ].…”