Variation In Metabolizing Enzymes Research Articles

Impact of CYP2D6 Pharmacogenomic Status on Pain Control Among Opioid-Treated Oncology Patients.

Several opioids have pharmacogenomic associations impacting analgesic efficacy. However, germline pharmacogenomic testing is not routinely incorporated into supportive oncology. We hypothesized that CYP2D6 profiling would correlate with opioid prescribing and hospitalizations. We analyzed 61,572 adult oncology patients from 2012 to 2018 for opioid exposures. CYP2D6 metabolizer phenotype (ultra-rapid [UM], normal metabolizer [NM], intermediate [IM], or poor [PM]), the latter two of which may cause inefficacy of codeine, tramadol, and standard-dose hydrocodone, was determined for patients genotyped for reasons unrelated to pain. The primary endpoint was number of opioid medications received during longitudinal care (IM/PMs vs. NMs). Secondary endpoint was likelihood of pain-related hospital encounters. Most patients with cancer (n= 34,675, 56%) received multiple opioids (average 2.8± 1.6/patient). Hydrocodone was most commonly prescribed (62%), followed by tramadol, oxycodone, and codeine. In the CYP2D6 genotyped cohort (n= 105), IM/PMs received a similar number of opioids (3.4± 1.4) as NMs (3.3± 1.9). However, IM/PMs were significantly more likely to experience pain-related hospital encounters compared with NMs, independent of other variables (odds ratio [OR]= 5.4; 95% confidence interval [CI], 1.2-23.6; p=.03). IM/PMs were also more likely to be treated with later-line opioids that do not require CYP2D6 metabolism, such as morphine and hydromorphone (OR=3.3; 95% CI, 1.1-9.8; p=.03). CYP2D6 genotype may identify patients with cancer at increased risk for inadequate analgesia when treated with typical first-line opioids like codeine, tramadol, or standard-dose hydrocodone. Palliative care considerations are an integral part of optimal oncology care, and these findings justify prospective evaluation of preemptive genotyping as a strategy to improve oncology pain management. Genomic variation in metabolic enzymes can predispose individuals to inefficacy when receiving opioid pain medications. Patients with intermediate and/or poor CYP2D6 metabolizer status do not adequately convert codeine, tramadol, and hydrocodone into active compounds, with resulting increased risk of inadequate analgesia. This study showed that patients with cancer frequently receive CYP2D6-dependent opioids. However, patients with CYP2D6 intermediate and poor metabolizer status had increased numbers of pain-related hospitalizations and more frequently required the potent non-CYP2D6 opioids morphine and hydromorphone. This may reflect inadequate initial analgesia with the common "first-line" CYP2D6-metabolized opioids. Preemptive genotyping to guide opioid prescribing during cancer care may improve pain-related patient outcomes.

Methylmercury exposure, genetic variation in metabolic enzymes, and the risk of glioma

Methylmercury (MeHg) is an environmental neurotoxin with human exposure mainly from dietary intake of contaminated fish. Exposure to MeHg has been implicated in neurological damage, but research on its role in cancers, specifically glioma, is limited. In a glioma case-control study, we examined associations between toenail mercury (Hg) and glioma risk. We also examined genetic polymorphisms in 13 genes related to MeHg metabolism for association with glioma risk; genetic associations were also studied in the UK Biobank cohort. Median toenail Hg in cases and controls, respectively, was 0.066 μg/g and 0.069 μg/g (interquartile range (IQR): 0.032–0.161 and 0.031–0.150 μg/g). Toenail Hg was not found to be significantly associated with glioma risk (Odds Ratio: 1.02; 95% Confidence Interval: 0.91, 1.14; p = 0.70 in analysis for ordinal trend with increasing quartile of toenail MeHg). No genetic variant was statistically significant in both of the studies; one variant, rs11859163 (MMP2) had a combined p-value of 0.02 though it was no longer significant after adjustment for multiple testing (Bonferroni corrected p = 1). This study does not support the hypothesis that exposure to MeHg plays a role in the development of glioma at levels of exposure found in this study population.

Genetic Basis of Idiosyncratic Responses to Alcoholism

Aim: The scientific viewpoint of genetic polymorphisms associated with risk of alcoholism and its adverse individual behavioural reactions is the main focus of this review. A complex syndrome like alcoholism and its idiosyncrasy may not be entirely understood on the basis of pathophysiological concept of neurotransmission alone. While neuropharmacology explains the mechanism behind molecular basis of alcoholism, the variation in alcohol induced abnormal neurotransmission due to presence or absence of different gene variants or isoenzymes of a particular gene on the other hand is a strong indication of genetic predisposition to alcoholism. In this article the term alcohol is used as a generic name for ethanol, which is the main subject of this discussion. Conclusion: The concomitant untoward intrinsic toxicity associated with alcoholism that makes it a potential trigger to a myriad of abnormal behavioural reactions in not only dose dependent pattern but with strong genetic disposition arises majorly due to different modes and levels of genetic variation in metabolic enzymes.

PP144—Assessing In Vivo Enzyme Genetic Variation in the Presence of Transporter Effect

PP144—ASSeSSiNg iN ViVo eNzyme geNeTiC VAriATioN iN The PreSeNCe of TrANSPorTer effeCT R. Chauhan; N. Tsamandouras; and A. Rostami-Hodjegan School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester; and Simcyp Ltd, Sheffield, United Kingdom Introduction: Interindividual variability in drug efficacy and toxicity can be partly attributed to genetic variation in metabolic enzymes, such as CYP2D6. The administration of probe substrates such as debrisoquine has been widely used in vivo to phenotype CYP2D6 metabolic activity. Recently, it was revealed that debrisoquine is also a substrate for the OCT1 uptake transporter. Therefore, the principal focus of this study was to analyze the misphenotyping that may arise in the complex situation, where drugs are substrates to both polymorphic enzymes and hepatic uptake transporters. Patients (or Materials) and Methods: A physiologically based pharmacokinetic modeling and simulation approach was carried out using the Simcyp Simulator (v12). A virtual study population (n = 1000) was generated including extensive, poor, and ultrarapid CYP2D6 metabolizers (86.5%, 8.2%, and 5.3% of the population, respectively). CYP2D6 activity was phenotyped using dextromethorphan as a probe substrate and monitoring indirect metrics such as the urinary recovery or plasma area under the curve metabolite/drug (dextrorphan/dextromethorphan) ratios. Multimodality in the frequency distribution of these metrics in the study population was assessed with the NTV (normal test variable) graphical method. Using a permeability-limited liver model and gradually decreasing the influx of the probe substrate into the liver, we investigated the effects of this decrease on the modality of the metrics frequency distribution. Results: Phenotyping successfully identified a clear multimodal frequency distribution in the study population with regard to CYP2D6 activity, when no hepatic permeability restrictions are applied to the probe substrate. However, when the uptake of the probe substrate into the liver is not passive but mainly transporter-mediated, the multimodality on the frequency distribution was clearly affected, confounding the distinction between the poor and extensive metabolizers. Specifically, when the contribution of the active uptake to total uptake was > 90%, multimodality was distorted to a unimodal frequency distribution. Conclusion: In conclusion, the findings suggest that when using a probe drug to phenotype the activity of a metabolic enzyme the hepatic permeability characteristics of the compound should be also considered. When uptake of the probe drug is predominately transporter mediated, influx into hepatocytes and not metabolism is the step that mostly contributes to the phenotype. Taking also into account that uptake transporters can also be polymorphically expressed the possibility that transporter variation can produce a flawed perception of enzyme activity should not be neglected. Disclosure of Interest: None declared.

The Human Mammary Gland as a Target for Isoflavones: How Does the Relation Vary in Individuals with Different Ethnicity?

Based on observational studies, it appears that soy food consumption provides protection against breast cancer primarily in Asian but not in Western populations. Given the problems in examining the effects of isoflavones directly in the human mammary gland, this review describes epidemiologic studies that investigated the association with biomarkers reflecting hormonal activity of isoflavones, in particular sex steroid levels, mammographic densities, nipple aspirate fluid, and tissue specimens from biopsies or surgeries. Three possible mechanisms that may be responsible for ethnic-specific health effects from these compounds are discussed: genetic variation in metabolic enzymes, timing of exposure, and intestinal metabolism by microbiota. Only a limited number of comparative studies and even fewer nutritional interventions have examined effects and addressed differences in biomarkers between Asian and Western populations. Investigations that looked at estrogens and mammographic densities as endpoints observed some associations in Asian women that were not seen in Caucasians. On the other hand, the low rate of nipple aspirate fluid production and a lack of breast tissue studies make it impossible to evaluate effects of isoflavones on these biomarkers in Asian women. Based on the current evidence, it appears likely that the timing of exposure is the most important determinant of beneficial health effects from soy foods. This may be the result of gut microbiota, which colonize the intestine during childhood and facilitates the hydrolysis of glycosides and the formation of equol from dadzein, a pathway that may result in beneficial health effects. The current evidence is insufficient to answer the question whether women of diverse ethnic groups experience distinct effects from soy isoflavones in breast tissue, but as knowledge about the role of early life nutrition and the development of gut microbiota increases, the potential for diverse metabolic pathways of isoflavones in individuals with different ethnic backgrounds and dietary exposures may be clarified.

Allometric scaling in centrarchid fish: origins of intra- and inter-specific variation in oxidative and glycolytic enzyme levels in muscle

The influence of body size on metabolic rate, muscle enzyme activities and the underlying patterns of mRNA for these enzymes were explored in an effort to explain the genetic basis of allometric variation in metabolic enzymes. We studied two pairs of sister species of centrarchid fish: black bass (largemouth bass Micropterus salmoides and smallmouth bass Micropterus dolomieui) and sunfish (pumpkinseed Lepomis gibbosus and bluegill Lepomis macrochirus). Our goal was to assess the regulatory basis of both intraspecific and interspecific variation relative to body size, as well as to gain insights into the evolutionary constraints within lineages. Whole animal routine metabolic rate showed scaling coefficients not significantly different from 1, ranging from (+0.87 to +0.96). However, there were significant effects of body size on the specific activities of oxidative and glycolytic enzymes. Mass-specific activity of the oxidative enzyme citrate synthase (CS) scaled negatively with body size in each species, with scaling coefficients ranging from -0.15 to -0.19, whereas the glycolytic enzyme pyruvate kinase (PK) showed positive scaling, with scaling coefficients ranging from +0.08 to +0.23. The ratio of mass-specific enzyme activity in PK to CS increased with body size, whereas the ratio of mRNA transcripts of PK to CS was unaffected, suggesting the enzyme relationships were not due simply to transcriptional regulation of both genes. The mass-dependent differences in PK activities were best explained by transcriptional regulation of the muscle PK gene; PK mRNA was a good predictor of PK specific enzyme activity within species and between species. Conversely, CS mRNA did not correlate with CS specific enzyme activities, suggesting post-transcriptional mechanisms may explain the observed inter-specific and intraspecific differences in oxidative enzymes.

Determination of Sequence Variants of Metabolizing Enzymes After Occupational Exposure to Fumes of Bitumen Under High Processing Temperatures

Data concerning the influence of sequence variants of metabolizing enzymes on the effect modulation of current exposure to fumes of bitumen in humans are limited. To assess effect modulation of genetic variants of metabolizing enzymes, 18 single nucleotide polymorphisms (SNPs) in metabolic enzymes were analyzed regarding their impact on the urinary levels of metabolites of polycyclic aromatic hydrocarbons. Based on personal ambient monitoring data for bitumen emissions a group of 180 workers exposed to fumes of bitumen under high processing temperatures during a shift were divided into two exposure groups: 24 with high exposure (> 10 mg/m3) and 156 with low (≤ 10 mg/m3) exposure. Additionally, 55 roadside construction workers without exposure to bitumen but with similar working tasks served as a reference group. SNP determination was performed by real-time PCR using the LightCycler technology based on DNA aliquots from blood samples. The impact of sequence variants on the urinary levels of 1-OH pyrene (1-OHP) and sum of OH-phenanthrenes (OHPhe) was estimated with mixed linear models, adjusted for exposure, smoking, and other factors. Bitumen exposure was a significant predictor of the urinary concentrations of 1-OHP and OHPhe. Both metabolite levels were modulated by the GG variant of the cytochrome P450 SNP CYP3A4 −392A > G , which showed increased levels of 1-OHP (p = 0.013) and OHPhe (p = 0.001). The GG variant of EPHX1 15543A > G showed a significant effect (p = 0.006) only on OHPhe. Selected variants of metabolic enzymes can modulate the metabolite levels under exposure to bitumen. The SNP-related modulation of these biomarkers did not exceed a factor of two and is more pronounced for OHPhe than for 1-OHP.

Receptor pharmacogenetics: relevance to CNS syndromes.

Pharmacogenetic research dedicated to the investigation of inherited factors that influence drug response has produced exciting results over the past decade. Adding to the knowledge that genetic variation in metabolic enzymes may cause drug-related adverse reactions, recent studies indicate that variation in neurotransmitter receptors can also be the cause of treatment failure. In addition, recent studies have attempted to use genetic information for the prediction of treatment outcome. The aim of this review is to summarize the most significant findings in pharmacogenetic research in relation to CNS drugs and to outline how these studies could lead to the individualization of drug treatment.

Interaction between smoking and glutathione S-transferase polymorphisms in solvent-induced chronic toxic encephalopathy.

Exposure to organic solvents is still common in industrial and other work environments, and increases the risk of chronic toxic encephalopathy (CTE). Genetic variation in metabolic enzymes for solvents and other xenobiotics may modify the risk of developing toxic effects. Therefore, we investigated the presence of null genotypes for glutathione S-transferases M1 and T1 (GSTM1, GSTT1) and two genetic polymorphisms of microsomal epoxide hydrolase (mEPHX) in relation to the risk for chronic toxic encephalopathy (CTE) when exposed to solvents and smoking. We genotyped 115 patients who were classified into three categories: CTE (n = 56), incipient CTE (n = 27) and non-CTE (n = 32) patients. DNA was isolated from leucocytes and the GSTM1 and GSTT1 null genotypes were determined by multiplex-polymerase chain reaction. The two polymorphisms of mEPHX were analysed by PCR-RFLP (restriction fragment length polymorphism) based assays. All analyses were performed blindly with regard to both exposure and disease status. An increased binomial regression risk ratio = 2.5, 95% confidence interval (CI) 1.5-4.2, of the GSTM1 null genotype for CTE was found in smokers and for the GSTT1 null genotype (binomial regression risk ratio 1.5, 95% CI 1.0-2.0). In nonsmokers, the GSTM1 null genotype did not confer any risk for CTE. None of the studied mEPHX polymorphisms were associated with an increased risk for CTE. We suggest that the GSTM1 null genotype in smokers is a possible risk for solvent-induced CTE.

Lack of association between allozymic variation and social dominance in free-living White-throated Sparrows

This study examined possible associations between allozymic variation in metabolic enzymes and social dominance or survival in a large free-living population of wintering White-throated Sparrows (Zonotrichia albicollis). Electrophoresis of 15 enzymes resolved from muscle biopsies from 173 sparrows revealed nine enzymes with some variation. Two of these (PGM and 6-PGD) showed substantial variation, with the frequency of the common allele below 0.9. During two seasons dominance interactions among the biopsied birds were observed at three feeding stations. There was no association between social dominance (percentage of opponents dominated) and genotype at the two most variable loci or overall proportion of heterozygotes at either the two most variable loci or the seven most consistently scored loci. Older birds were more likely than expected to be heterozygous at both the PGM and 6-PGD loci, but heterozygotes did not return more frequently than homozygotes in subsequent years. Although we cannot exclude a weak association of dominance and isozyme variability, we can conclude that social dominance during winter lacks any strong relationship with variation at loci for metabolic enzymes.