CYP2D6 is of great importance for the metabolism of clinically used drugs and about 20–25% of those are metabolised by this enzyme. In addition, the enzyme utilises hydroxytryptamines as endogenous substrates. The polymorphism of the enzyme results in poor, intermediate, efficient or ultrarapid metabolisers (UMs) of CYP2D6 drugs. It is plausible that the UM genotype, where more than one active gene on one allele occurs, is the outcome of selective dietary selection in certain populations in North East Africa. The UM phenotype affects 5.5% of the population in Western Europe. A hypothesis for the evolutionary basis behind selection for CYP2D6 gene duplications is presented in relation to selection for Cyp6 variants in insecticide resistant Drosophila strains. The polymorphism of CYP2D6 significantly affects the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The consequences of the polymorphism at ordinary drug doses can be either adverse drug reactions or no drug response. Examples are presented where CYP2D6 polymorphism affects the efficacy and costs of drug treatment. Predictive CYP2D6 genotyping is estimated by the author to be beneficial for treatment of about 30–40% of CYP2D6 drug substrates, that is, for about 7–10% of all drugs clinically used, although prospective clinical studies are necessary to evaluate the exact benefit of drug selection and dosage based on the CYP2D6 genotype.

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Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity

Differences in drug responsiveness are common, often leading to challenges in optimizing the dosage regimen for a particular patient. Recent advances provide a rational framework for understanding many interpatient differences in drug disposition and their clinical consequences. This article focuses on the cytochrome P-450 enzymes, a superfamily of microsomal drug-metabolizing enzymes that play an important role in oxidative drug metabolism.

Drug metabolism and variability among patients in drug response

Of about one dozen human P450 s that catalyze biotransformations of xenobiotics, CYP2D6 is one of the more important ones based on the number of its drug substrates. It shows a very high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences expression and function. This so-called debrisoquine/sparteine oxidation polymorphism has been extensively studied in many different populations and over 80 alleles and allele variants have been described. CYP2D6 protein and enzymatic activity is completely absent in less than 1% of Asian people and in up to 10% of Caucasians with two null alleles, which do not encode a functional P450 protein product. The resulting "poor metabolizer" (PM) phenotype is characterized by the inability to use CYP2D6-dependent metabolic pathways for drug elimination, which affect up to 20% of all clinically used drugs. The consequences are increased risk of adverse drug reactions or lack of therapeutic response. Today, genetic testing predicts the PM phenotype with over 99% certainty. At the other extreme, the "Ultrarapid Metabolizer" (UM) phenotype can be caused by alleles carrying multiple gene copies. "Intermediate Metabolizers" (IM) are severely deficient in their metabolism capacity compared to normal "Extensive Metabolizers" (EM), but in contrast to PMs they express a low amount of residual activity due to the presence of at least one partially deficient allele. Whereas the intricate genetics of the CYP2D6 polymorphism is becoming apparent at ever greater detail, applications in clinical practice are still rare. More clinical studies are needed to show where patients benefit from drug dose adjustment based on their genotype. Computational approaches are used to predict and rationalize substrate specificity and enzymatic properties of CYP2D6. Pharmacophore modeling of ligands and protein homology modeling are two complementary approaches that have been applied with some success. CYP2D6 is not only expressed in liver but also in the gut and in brain neurons, where endogenous substrates with high-turnover have been found. Whether and how brain functions may be influenced by polymorphic expression are interesting questions for the future.

Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry

Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions. Although genotype tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes.

The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects.

Cytochrome P450 (CYP) 2D6 is one of the most investigated CYPs in relation to genetic polymorphism, but accounts for only a small percentage of all hepatic CYPs (∼2–4%). There is a large interindividual variation in the enzyme activity of CYP2D6. The enzyme is largely non-inducible and metabolizes ∼25% of current drugs. Typical substrates for CYP2D6 are largely lipophilic bases and include some antidepressants, antipsychotics, antiarrhythmics, antiemetics, β-adrenoceptor antagonists (β-blockers) and opioids. The CYP2D6 activity ranges considerably within a population and includes ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). There is a considerable variability in the CYP2D6 allele distribution among different ethnic groups, resulting in variable percentages of PMs, IMs, EMs and UMs in a given population. To date, 74 allelic variants and a series of subvariants of the CYP2D6 gene have been reported and the number of alleles is still growing. Among these are fully functional alleles, alleles with reduced function and null (non-functional) alleles, which convey a wide range of enzyme activity, from no activity to ultrarapid metabolism of substrates. As a consequence, drug adverse effects or lack of drug effect may occur if standard doses are applied. The alleles *10, *17, *36 and *41 give rise to substrate-dependent decreased activity. Null alleles of CYP2D6 do not encode a functional protein and there is no detectable residual enzymatic activity. It is clear that alleles *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42, *44, *56 and *62 have no enzyme activity. They are responsible for the PM phenotype when present in homozygous or compound heterozygous constellations. These alleles are of clinical significance as they often cause altered drug clearance and drug response. Among the most important variants are CYP2D6*2, *3, *4, *5, *10, *17 and *41. On the other hand, the CYP2D6 gene is subject to copy number variations that are often associated with the UM phenotype. Marked decreases in drug concentrations have been observed in UMs with tramadol, venlafaxine, morphine, mirtazapine and metoprolol. The functional impact of CYP2D6 alleles may be substrate-dependent. For example, CYP2D6*17 is generally considered as an allele with reduced function, but it displays remarkable variability in its activity towards substrates such as dextromethorphan, risperidone, codeine and haloperidol. The clinical consequence of the CYP2D6 polymorphism can be either occurrence of adverse drug reactions or altered drug response. Drugs that are most affected by CYP2D6 polymorphisms are commonly those in which CYP2D6 represents a substantial metabolic pathway either in the activation to form active metabolites or clearance of the agent. For example, encainide metabolites are more potent than the parent drug and thus QRS prolongation is more apparent in EMs than in PMs. In contrast, propafenone is a more potent b-blocker than its metabolites and the β-blocking activity during propafenone therapy is more prominent in PMs than EMs, as the parent drug accumulates in PMs. Since flecainide is mainly eliminated through renal excretion, and both R- and S-flecainide possess equivalent potency for sodium channel inhibition, the CYP2D6 phenotype has a minor impact on the response to flecainide. Since the contribution of CYP2D6 is greater for metoprolol than for carvedilol, propranolol and timolol, a stronger gene-dose effect is seen with this β-blocker, while such an effect is lesser or marginal in other β-blockers. Concordant genotype-phenotype correlation provides a basis for predicting the phenotype based on genetic testing, which has the potential to achieve optimal pharmacotherapy. However, genotype testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding genotype-phenotype, gene-concentration and gene-dose relationships. Further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts of subjects.

Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II.

With the rapid developments in the exoplanet field, more and more terrestrial exoplanets are being detected. Characterising their atmospheres using transit observations will become a key datum in the quest for detecting an Earth-like exoplanet. The atmospheric transmission spectrum of our Earth will be an ideal template for comparison with future exo-Earth candidates. By observing a lunar eclipse, which offers a similar configuration to that of an exoplanet transit, we have obtained a high resolution and high signal-to-noise ratio transmission spectrum of the Earth's atmosphere. This observation was performed with the High Resolution Spectrograph at Xinglong Station, China during the total lunar eclipse in December 2011. We compare the observed transmission spectrum with our atmospheric model, and determine the characteristics of the various atmospheric species in detail. In the transmission spectrum, O2, O3, O2-O2, NO2 and H2O are detected, and their column densities are measured and compared with the satellites data. The visible Chappuis band of ozone produces the most prominent absorption feature, which suggests that ozone is a promising molecule for the future exo-Earth characterization. The individual O2 lines are resolved and O2 isotopes are clearly detected. Our new observations do not confirm the absorption features of Ca II or Na I which have been reported in previous lunar eclipse observations. However, features in these and some other strong Fraunhofer line positions do occur in the observed spectrum. We propose that these are due to a Raman-scattered component in the forward-scattered sunlight appearing in the lunar umbral spectrum. Water vapour absorption is found to be rather weak in our spectrum because the atmosphere we probed is relatively dry, which prompts us to discuss the detectability of water vapour in Earth-like exoplanet atmospheres.

High resolution transmission spectrum of the Earth's atmosphere -- Seeing Earth as an exoplanet using a lunar eclipse

Transit spectroscopy is the most frequently used technique to reveal the atmospheric properties of exoplanets, while that at high resolution has the advantage to resolve the small Doppler shift of spectral lines, and the trace signal of the exoplanet atmosphere can be separately extracted. We obtain the transmission spectra of the extrasolar planet WASP-85Ab, a hot Jupiter in a 2.655-day orbit around a G5, V=11.2 mag host star, observed by high-resolution spectrograph ESPRESSO at the Very Large Telescope array for three transits. We present an analysis of the Rossiter-McLaughlin effect on WASP-85A, and determine a spin-orbit angle ${\lambda = -16.155^{\circ}}^{+2.916}_{-2.879}$, suggesting that the planet is in an almost aligned orbit. Combining the transmission spectra of three nights, we tentatively detected H$\alpha$ and Ca II absorption with $\gtrapprox 3\sigma$ via direct visual inspection of the transmission spectra with the Center-to-Limb variation and the Rossiter-McLaughlin effects removed, which still remain visible after excluding the cores of these strong lines with a 0.1 A mask. These spectral signals seems likely to origin from the planetary atmosphere, but we can not fully exclude their stellar origins. Via the cross-correlation analysis of a set of atoms and molecules, Li I is marginally detected at $\sim4\sigma$ level, suggesting that Li might be present in the atmosphere of WASP-85Ab.

Atmospheric composition of WASP-85Ab with ESPRESSO/VLT observations

Ultra-hot Jupiters are defined as giant planets with equilibrium temperatures larger than 2000 K. Most of them are found orbiting bright A-F type stars, making them extremely suitable objects to study their atmospheres using high-resolution spectroscopy. Recent studies show a variety of atoms and molecules detected in the atmospheres of this type of planets. Here we present our analysis of the newly discovered ultra-hot Jupiter TOI-1431b/MASCARA-5b, using two transit observations with the HARPS-N spectrograph and one transit observation with the EXPRES spectrograph. Analysis of the Rossiter-McLaughlin effect shows that the planet is in a polar orbit, with a projected obliquity $ \lambda = -155^{+20}_{-10}$ degrees. Combining the nights and applying both cross-correlation methods and transmission spectroscopy, we find no evidences of CaI, FeI, FeII, MgI, NaI, VI, TiO, VO or H$\alpha$ in the atmosphere of the planet. Our most likely explanation for the lack of atmospheric features is the large surface gravity of the planet.

The obliquity and atmosphere of the ultra-hot Jupiter TOI-1431b (MASCARA-5b): A misaligned orbit and no signs of atomic ormolecular absorptions

Hot giant planets like MASCARA-1 b are expected to have thermally inverted atmospheres, that makes them perfect laboratory for the atmospheric characterization through high-resolution spectroscopy. Nonetheless, previous attempts of detecting the atmosphere of MASCARA-1 b in transmission have led to negative results. In this paper we aim at the detection of the optical emission spectrum of MASCARA-1 b. We used the high-resolution spectrograph PEPSI to observe MASCARA-1 (spectral type A8) near the secondary eclipse of the planet. We cross-correlated the spectra with synthetic templates computed for several atomic and molecular species. We obtained the detection of FeI, CrI and TiI in the atmosphere of MASCARA-1 b with a S/N ~7, 4 and 5 respectively, and confirmed the expected systemic velocity of ~13 km/s and the radial velocity semi-amplitude of MASCARA-1 b of ~200 km/s. The detection of Ti is of particular importance in the context of the recently proposed Ti cold-trapping below a certain planetary equilibrium temperature. We confirm the presence of an the atmosphere around MASCARA-1 b through emission spectroscopy. We conclude that the atmospheric non detection in transmission spectroscopy is due to the high gravity of the planet and/or to the overlap between the planetary track and its Doppler shadow.

The PEPSI Exoplanet Transit Survey (PETS). III. The detection of Fe i, Cr i, and Ti i in the atmosphere of MASCARA-1 b through high-resolution emission spectroscopy

Fei Yan

Papers

High resolution transmission spectrum of the Earth's atmosphere -- Seeing Earth as an exoplanet using a lunar eclipse

Atmospheric composition of WASP-85Ab with ESPRESSO/VLT observations

The obliquity and atmosphere of the ultra-hot Jupiter TOI-1431b (MASCARA-5b): A misaligned orbit and no signs of atomic ormolecular absorptions

The PEPSI Exoplanet Transit Survey (PETS). III. The detection of Fe i, Cr i, and Ti i in the atmosphere of MASCARA-1 b through high-resolution emission spectroscopy