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Figure 1. CYP1A2 gene and the location of the SNPs that are described in CYP1A2 allele nomenclature.
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CYP1A2 enzyme expression & substrates
The CYP enzyme superfamily is involved in the biotransformation of exogenous and endogenous compounds and accounts for most of phase I drug metabolism [1]. Among the clinically important members, the CYP1A subfamily constitutes approximately 15% of the total liver CYP content [2]. Human CYP1A1 is expressed mainly in extrahepatic tissues such as lung, skin, larynx and placenta, while CYP1A2 is exclusively expressed in the liver [2]. The CYP1A2 gene is believed to have arisen via duplication of CYP1A1 approximately 350 million years ago during the evolution of mammals and birds, functioning in the detoxification of environmental xenobiotics [3,4].
Substrates of the CYP1A2 enzyme are characteristically planar molecules with polyaromatic rings that fit the narrow and planar active-site architecture of the enzyme [5,6]. The CYP1A2 enzyme plays a key role in the metabolism of various drugs, such as clozapine [7,8], olanzapine [9,10], flutamide [11], lidocaine [12], tizanidine [13] and tacrine [14,15]. CYP1A2 is also involved in the biotransformation of some endogenous compounds, such as melatonin [16,17], estrone and estradiol [18], bilirubin [19] and uroporphyrinogen [20], as well as the bioactivation of procarcinogens, such as aromatic, heterocyclic amines, polycyclic aromatic hydrocarbons and aflatoxin B1 [21--25]. Box 1 summarizes the substrates, inducers and inhibitors of CYP1A2.
Probe substrates for CYP1A2 activity
The well-known CYP1A2 substrate caffeine is widely present in daily-consumed beverages, such as coffee, tea and soft drinks, and in chocolate. Demethylation accounts for 80% of caffeine''s systemic clearance [22,26]. Caffeine clearance is considered to be ''gold standard'' for CYP1A2 activity, and CYP1A2-mediated reactions in caffeine metabolism have been used to phenotype the activity of this enzyme [27,28]. Oral caffeine clearance correlates well with the metabolic ratio 17X:137X in saliva (r s = 0.82) and plasma (rs = 0.82), 4 h after caffeine consumption, where 17X is 1,7-dimethylxanthine (paraxanthine), the major caffeine metabolite, and 137X is 1,3,7-trimethylxanthine (caffeine) [29]. CYP1A2 is also involved in the further metabolism of paraxanthine to 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1,7-dimethyluric acid (17U), 1-methyluracil (1U) and 1-methylxanthine (1X) [30]. Although renal blood flow, renal function and urine flow might influence the metNSabolic ratios based on urine...