Genetic variation in UGT1A1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials.

Introduction: Bioequivalence clinical trials are conducted in healthy volunteers whose blood tests should be within normal limits; individuals with Gilbert syndrome (GS) are excluded from these studies on suspicion of any liver disease, even if the change is clinically insignificant. GS is a benign genetic disorder characterized by elevated bilirubin levels, the primary cause of which is the presence of polymorphisms in UGT1A1 gene. In this work, subjects with UGT1A1 intermediate (IM) or poor (PM) metabolizer genotype-informed phenotypes were investigated to determine whether they have a higher incidence of liver disease or other biochemical parameters. Methods: The study population comprised 773 healthy volunteers who underwent biochemical analysis at baseline and at the end of the study which were genotyped for UGT1A1*80 (rs887829), as an indicator of UGT1A1*80+*28 (rs887829 and rs3064744), and UGT1A1*6 (rs4148323). Results: Bilirubin levels were higher in subjects IMs and PMs compared to normal metabolizers (NMs). Decreased uric acid levels was observed in PMs compared to NMs. No associations were observed in liver enzyme levels according to UGT1A1 phenotype. Discussion: Considering that there is no hepatic toxicity in subjects with UGT1A1 IM or PM phenotype, who are more likely to develop GS, this study suggests that they could be included in bioequivalence clinical trials as their biochemical parameters are not affected outside normal ranges.

Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide.

Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters' genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach it (tmax), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan tmax compared to those with T/G and G/G genotypes (p < 0.001, ß = 0.821, R2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC∞/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, ß = 1047.35, R2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics.

Genetic Variation in CYP2D6 and SLC22A1 Affects Amlodipine Pharmacokinetics and Safety.

Amlodipine is an antihypertensive drug with unknown pharmacogenetic biomarkers. This research is a candidate gene study that looked for associations between amlodipine pharmacokinetics and safety and pharmacogenes. Pharmacokinetic and safety data were taken from 160 volunteers from eight bioequivalence trials. In the exploratory step, 70 volunteers were genotyped for 44 polymorphisms in different pharmacogenes. CYP2D6 poor metabolizers (PMs) showed higher half-life (t1/2) (univariate p-value (puv) = 0.039, multivariate p-value (pmv) = 0.013, ß = -5.31, R2 = 0.176) compared to ultrarapid (UMs), normal (NMs) and intermediate metabolizers (IMs). SLC22A1 rs34059508 G/A genotype was associated with higher dose/weight-corrected area under the curve (AUC72/DW) (puv = 0.025; pmv = 0.026, ß = 578.90, R2 = 0.060) compared to the G/G genotype. In the confirmatory step, the cohort was increased to 160 volunteers, who were genotyped for CYP2D6, SLC22A1 and CYP3A4. In addition to the previous associations, CYP2D6 UMs showed a lower AUC72/DW (puv = 0.046, pmv = 0.049, ß = -68.80, R2 = 0.073) compared to NMs, IMs and PMs and the SLC22A1 rs34059508 G/A genotype was associated with thoracic pain (puv = 0.038) and dizziness (puv = 0.038, pmv = 0.014, log OR = 10.975). To our knowledge, this is the first work to report a strong relationship between amlodipine and CYP2D6 and SLC22A1. Further research is needed to gather more evidence before its application in clinical practice.

Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine.

Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study was to evaluate the impact of 29 alleles in 12 candidate genes (e.g., CYP enzymes like CYP2D6, CYP3A4, or CYP2C19; ABC transporters like ABCB1; SLCO1B1; and UGT enzymes like UGT1A1) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials (n = 98) evaluating desvenlafaxine formulations (five with single dose administration and one with multiple-dose administration) were analyzed. No genetic polymorphism was related to pharmacokinetic variability or ADR incidence. Volunteers enrolled in the multiple-dose clinical trial also showed a higher incidence of ADRs, e.g., xerostomia or appetite disorders. Volunteers experiencing any ADR showed a significantly higher area under the time-concentration curve (AUC) than those not experiencing any ADR (5115.35 vs. 4279.04 ng*h/mL, respectively, p = 0.034). In conclusion, the strong dose-dependent relationship with the occurrence of ADRs confirms that the mechanism of action of desvenlafaxine is essentially dose-dependent.

Polymorphism of Drug Transporters, Rather Than Metabolizing Enzymes, Conditions the Pharmacokinetics of Rasagiline.

Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson's disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in other CYP enzymes (e.g., CYP2C19), UGT enzymes (e.g., UGT1A1) or other enzymes (e.g., NAT2), and transporters (e.g., SLCO1B1) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. CYP1A2 alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with ABCB1 rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC0-∞/DW) than those with the G/G genotype (p = 0.012) and lower volume of distribution (Vd/F) and clearance (Cl/F) (p = 0.001 and p = 0.012, respectively). Subjects with the ABCC2 rs2273697 A/A genotype presented lower tmax (i.e., the time to reach the maximum concentration, Cmax) compared to those with G/G+G/A genotypes (p = 0.001). Volunteers with the SLC22A1 *1/*5 genotype exhibited lower Cmax/DW and higher tmax (p = 0.003 and p = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline.

Environmental risks from artificial nighttime lighting widespread and increasing across Europe.

The nighttime environment of much of Earth is being changed rapidly by the introduction of artificial lighting. While data on spatial and temporal variation in the intensity of artificial lighting have been available at a regional and global scale, data on variation in its spectral composition have only been collected for a few locations, preventing variation in associated environmental and human health risks from being mapped. Here, we use imagery obtained using digital cameras by astronauts on the International Space Station to map variation in the spectral composition of lighting across Europe for 2012-2013 and 2014-2020. These show a regionally widespread spectral shift, from that associated principally with high-pressure sodium lighting to that associated with broad white light-emitting diodes and with greater blue emissions. Reexpressing the color maps in terms of spectral indicators of environmental pressures, we find that this trend is widely increasing the risk of harmful effects to ecosystems.

Pervasiveness of Biological Impacts of Artificial Light at Night.

Artificial light at night (ALAN) and its associated biological impacts have regularly been characterized as predominantly urban issues. Although far from trivial, this would imply that these impacts only affect ecosystems that are already heavily modified by humans and are relatively limited in their spatial extent, at least as compared with some key anthropogenic pressures on the environment that attract much more scientific and public attention, such as climate change or plastic pollution. However, there are a number of reasons to believe that ALAN and its impacts are more pervasive, and therefore need to be viewed from a broader geographic perspective rather than an essentially urban one. Here we address, in turn, 11 key issues when considering the degree of spatial pervasiveness of the biological impacts of ALAN. First, the global extent of ALAN is likely itself commonly underestimated, as a consequence of limitations of available remote sensing data sources and how these are processed. Second and third, more isolated (rural) and mobile (e.g., vehicle headlight) sources of ALAN may have both very widespread and important biological influences. Fourth and fifth, the occurrence and impacts of ALAN in marine systems and other remote settings, need much greater consideration. Sixth, seventh, and eighth, there is growing evidence for important biological impacts of ALAN at low light levels, from skyglow, and over long distances (because of the altitudes from which it may be viewed by some organisms), all of which would increase the areas over which impacts are occurring. Ninth and tenth, ALAN may exert indirect biological effects that may further expand these areas, because it has a landscape ecology (modifying movement and dispersal and so hence with effects beyond the direct extent of ALAN), and because ALAN interacts with other anthropogenic pressures on the environment. Finally, ALAN is not stable, but increasing rapidly in global extent, and shifting toward wavelengths of light that often have greater biological impacts.

Association Between Outdoor Light-at-night Exposure and Colorectal Cancer in Spain.

BACKGROUND: Night-shift work, exposure to artificial light-at-night (ALAN) and particularly blue light spectrum, and the consequent circadian disruption may increase the risk of breast and prostate cancer. Colorectal cancer risk may also be increased among night-shift workers. We investigated the association between exposure to ALAN according to light spectrum and colorectal cancer among subjects who had never worked at night in a general population case-control study in Spain. METHODS: We examined information on 661 incident histologically verified colorectal cancer cases and 1,322 controls from Barcelona and Madrid, 2007-2013. Outdoor ALAN exposure was based on images from the International Space Station (ISS) including data on remotely sensed upward light intensity. We derived adjusted odds ratio (OR) estimates and confidence intervals (CI) for visual light, blue light, and spectral sensitivities of the five human photopigments assigned to participant's geocoded longest residence. RESULTS: Exposure to blue light spectrum was positively associated with colorectal cancer (OR = 1.6; 95% CI: 1.2-2.2; highest vs. lowest tertile). ORs were similar (OR = 1.7; 95% CI: 1.3-2.3) when further adjusting for area socioeconomic status, diet patterns, smoking, sleep, and family history. We observed no association for outdoor visual light (full spectrum) (OR = 1.0; 95% CI, 0.7-1.2; highest vs. lowest tertile). Analysis of the five photopigments gave similar results with increased risks for shorter wavelengths overlapping with the blue spectrum and no association for longer wavelengths. CONCLUSIONS: Outdoor blue light spectrum exposure that is increasingly prevalent in recent years may be associated with colorectal cancer risk. See video abstract: http://links.lww.com/EDE/B708.

The nature of the diffuse light near cities detected in nighttime satellite imagery.

Diffuse glow has been observed around brightly lit cities in nighttime satellite imagery since at least the first publication of large scale maps in the late 1990s. In the literature, this has often been assumed to be an error related to the sensor, and referred to as "blooming", presumably in relation to the effect that can occur when using a CCD to photograph a bright light source. Here we show that the effect seen on the DMSP/OLS, SNPP/VIIRS-DNB and ISS is not only instrumental, but in fact represents a real detection of light scattered by the atmosphere. Data from the Universidad Complutense Madrid sky brightness survey are compared to nighttime imagery from multiple sensors with differing spatial resolutions, and found to be strongly correlated. These results suggest that it should be possible for a future space-based imaging radiometer to monitor changes in the diffuse artificial skyglow of cities.

Evaluating Human Photoreceptoral Inputs from Night-Time Lights Using RGB Imaging Photometry.

Night-time lights interact with human physiology through different pathways starting at the retinal layers of the eye; from the signals provided by the rods; the S-, L- and M-cones; and the intrinsically photosensitive retinal ganglion cells (ipRGC). These individual photic channels combine in complex ways to modulate important physiological processes, among them the daily entrainment of the neural master oscillator that regulates circadian rhythms. Evaluating the relative excitation of each type of photoreceptor generally requires full knowledge of the spectral power distribution of the incoming light, information that is not easily available in many practical applications. One such instance is wide area sensing of public outdoor lighting; present-day radiometers onboard Earth-orbiting platforms with sufficient nighttime sensitivity are generally panchromatic and lack the required spectral discrimination capacity. In this paper, we show that RGB imagery acquired with off-the-shelf digital single-lens reflex cameras (DSLR) can be a useful tool to evaluate, with reasonable accuracy and high angular resolution, the photoreceptoral inputs associated with a wide range of lamp technologies. The method is based on linear regressions of these inputs against optimum combinations of the associated R, G, and B signals, built for a large set of artificial light sources by means of synthetic photometry. Given the widespread use of RGB imaging devices, this approach is expected to facilitate the monitoring of the physiological effects of light pollution, from ground and space alike, using standard imaging technology.

Evaluating the Association between Artificial Light-at-Night Exposure and Breast and Prostate Cancer Risk in Spain (MCC-Spain Study).

BACKGROUND: Night shift work, exposure to light at night (ALAN) and circadian disruption may increase the risk of hormone-dependent cancers. OBJECTIVES: We evaluated the association of exposure to ALAN during sleeping time with breast and prostate cancer in a population based multicase-control study (MCC-Spain), among subjects who had never worked at night. We evaluated chronotype, a characteristic that may relate to adaptation to light at night. METHODS: We enrolled 1,219 breast cancer cases, 1,385 female controls, 623 prostate cancer cases, and 879 male controls from 11 Spanish regions in 2008-2013. Indoor ALAN information was obtained through questionnaires. Outdoor ALAN was analyzed using images from the International Space Station (ISS) available for Barcelona and Madrid for 2012-2013, including data of remotely sensed upward light intensity and blue light spectrum information for each geocoded longest residence of each MCC-Spain subject. RESULTS: Among Barcelona and Madrid participants with information on both indoor and outdoor ALAN, exposure to outdoor ALAN in the blue light spectrum was associated with breast cancer [adjusted odds ratio (OR) for highest vs. lowest tertile, OR=1.47; 95% CI: 1.00, 2.17] and prostate cancer (OR=2.05; 95% CI: 1.38, 3.03). In contrast, those exposed to the highest versus lowest intensity of outdoor ALAN were more likely to be controls than cases, particularly for prostate cancer. Compared with those who reported sleeping in total darkness, men who slept in "quite illuminated" bedrooms had a higher risk of prostate cancer (OR=2.79; 95% CI: 1.55, 5.04), whereas women had a slightly lower risk of breast cancer (OR=0.77; 95% CI: 0.39, 1.51). CONCLUSION: Both prostate and breast cancer were associated with high estimated exposure to outdoor ALAN in the blue-enriched light spectrum. https://doi.org/10.1289/EHP1837.

Artificially lit surface of Earth at night increasing in radiance and extent.

A central aim of the "lighting revolution" (the transition to solid-state lighting technology) is decreased energy consumption. This could be undermined by a rebound effect of increased use in response to lowered cost of light. We use the first-ever calibrated satellite radiometer designed for night lights to show that from 2012 to 2016, Earth's artificially lit outdoor area grew by 2.2% per year, with a total radiance growth of 1.8% per year. Continuously lit areas brightened at a rate of 2.2% per year. Large differences in national growth rates were observed, with lighting remaining stable or decreasing in only a few countries. These data are not consistent with global scale energy reductions but rather indicate increased light pollution, with corresponding negative consequences for flora, fauna, and human well-being.

Zernike analysis of all-sky night brightness maps.

All-sky night brightness maps (calibrated images of the night sky with hemispherical field-of-view (FOV) taken at standard photometric bands) provide useful data to assess the light pollution levels at any ground site. We show that these maps can be efficiently described and analyzed using Zernike circle polynomials. The relevant image information can be compressed into a low-dimensional coefficients vector, giving an analytical expression for the sky brightness and alleviating the effects of noise. Moreover, the Zernike expansions allow us to quantify in a straightforward way the average and zenithal sky brightness and its variation across the FOV, providing a convenient framework to study the time course of these magnitudes. We apply this framework to analyze the results of a one-year campaign of night sky brightness measurements made at the UCM observatory in Madrid.