Phenotype prediction of nonsynonymous single nucleotide polymorphisms in human phase II drug/xenobiotic metabolizing enzymes: perspectives on molecular evolution

Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions can lead to amino acid changes that might alter the protein’s function and account for susceptibility to disease and altered drug/xenobiotic response. Many nsSNPs have been found in genes encoding human phase II metabolizing enzymes; however, there is little known about the relationship between the genotype and phenotype of nsSNPs in these enzymes. We have identified 923 validated nsSNPs in 104 human phase II enzyme genes from the Ensembl genome database and the NCBI SNP database. Using PolyPhen, Panther, and SNAP algorithms, 44%?59% of nsSNPs in phase II enzyme genes were predicted to have functional impacts on protein function. Predictions largely agree with the available experimental annotations. 68% of deleterious nsSNPs were correctly predicted as damaging. This study also identified many amino acids that are likely to be functionally critical, but have not yet been studied experimentally. There was significant concordance between the predicted results of Panther and PolyPhen, and between SNAP non-neutral predictions and PolyPhen scores. Evolutionarily non-neutral (destabilizing) amino acid substitutions are thought to be the pathogenetic basis for the alteration of phase II enzyme activity and to be associated with disease susceptibility and drug/xenobiotic toxicity. Furthermore, the molecular evolutionary patterns of phase II enzymes were characterized with regards to the predicted deleterious nsSNPs.

Self-medication with nutritional supplements and herbal over-the-counter products

In recent years,the popularity increased for nutritional supplements and herbal products.Prescription drugs,but not herbal therapies are paid by health insurances.They are sold over-the-counter(OTC)on the patients’own expense.However,there are potential risks of self-medication,e.g.incorrect self-diagnosis,severe adverse reactions,dangerous drug interactions,risk of addiction etc.They are often used by patients at their own discretion without knowledge of and control by their physicians.Certain users are at risk of intoxication.Multiple medications taken by older patients increase the risk for adverse drug reactions,drug-drug interactions,and compliance problems for this age group(polypharmacy).Herbals should be discontinued prior to operations to avoid interactions with anesthetics or anticoagulants.Herbal preparations may also be carcinogenic or interfere with cancer treatments.Pregnant women use various OTC preparations.However,in many cases,it is unclear whether their use is safe for mother or baby.Self-medication with herbals is also largely distributed among anxious and depressive patients,and patients with other conditions and symptoms.The popularity of herbal products has also brought concerns on quality,efficacy and safety.Cases of botanical misidentification,contaminations with heavy metals,pesticides,radioactivity,organic solvents,microbials as well as adulteration with chemical drugs necessitate the establishment of international quality control standards.Hepatotoxic effects have been reported for more than 300 plant species,and some commonly used herbs have been demonstrated to interact with Western medication.Health care professionals have a critical responsibility assessing the self-care ability of their patients.Databases are available for pharmacists with information on action,side effects and toxicities as well as herbdrug interactions.There is a need for established guidelines regarding the correct use of nutritional supplements and herbal OTC preparations(phytovigilance).Physicians,pharmacists,and other health care professionals have to counsel patients and the general public on the benefits and risks associated with herbal drugs.Information centers for consumers and general practitioners are needed,and convincing evidence on safety and efficacy of herbal products has to be demonstrated in placebo-controlled,double blind and randomized clinical trials.