Pharmacogenetics of drug-metabolizing enzymes in Italian populations

Abstract

: Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Inter-individual differences in genes coding for drug-metabolizing enzymes are important for understanding variability in drug response and for individualization of drug prescription. The prevalence of genetic polymorphisms in drug metabolism varies widely with ethnicity, and marked differences in the distribution of allelic variants of genes encoding drug-metabolizing enzymes have been documented in populations of different racial origin. This review aimed to summarize the available studies on genetic polymorphisms associated with drug metabolism conducted in Italian populations and to compare the frequency of the various metabolizer phenotypes and most common variant alleles (and resulting genotypes) with corresponding values from other populations. Notably, published data are not extensive, and most studies were performed on relatively low numbers of individuals. In general, the frequency of polymorphisms in the cytochrome P450 ( CYP ) genes as well as in the investigated phase II enzymes in the Italian population was similar to values reported for other Caucasian populations. However, the prevalence of CYP2D6 gene duplication among Italians was found to be very high, confirming the higher frequency of CYP2D6 ultrarapid metabolizers in the Mediterranean area compared to Northern Europe. It is worth noting that a geographic gradient in the flavin-containing monooxygenase 3 polymorphism distribution was also seen, the Italian population showing higher similarity to other Mediterranean populations than to North Europeans.

Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species

“…However, only the 1, 2, and 3 CYP families are involved in phase I drug metabolism. CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 are the CYP isoforms which function in the metabolism of therapeutic agents [23]. The production of ROS arises from the release of superoxide anion radical due to the decay of the one-electron-reduced ternary complex and the protonation of the CYP with the formation of hydrogen peroxide [24].…”

Effects of 22 Novel CYP2D6 Variants Found in the Chinese Population on the Bufuralol and Dextromethorphan Metabolisms In Vitro

“…In contrast, oriental populations exhibit significantly lower PM frequencies (<1%) relative to white populations . Among the non‐functional alleles that have been reported thus far, CYP2D6*3, CYP2D6*4, CYP2D6*5 and CYP2D6*6 are the major alleles that are associated with the PM phenotype and account for ~98% of Caucasian PMs . However, these alleles, with the exception of CYP2D6*5, have been reported to play less important roles in Asians due to their low frequencies .…”

Inter‐individual and inter‐regional variations in enteric drug metabolizing enzyme activities: Results with cryopreserved human intestinal mucosal epithelia (CHIM) from the small intestines of 14 donors

“…Most investigations on individual differences in drug metabolism, a major contributing factor to inter‐individual differences in drug efficacy and toxicity, are focused on liver metabolism 62‐72 . Our results with CHIM from the duodenum, jejunum, and ileum from 10 donors show that P450 isoforms, UGT, SULT, and NAT1, demonstrated relatively large inter‐individual variations for all three regions of the small intestine, with specific activities differing by more than three orders of magnitude.…”