Philip Lazarus's research while affiliated with Washington State University and other places

Publications (332)

Article
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Cannabis-based products have experienced notable increases in co-usage alongside tobacco products. Several cannabinoids exhibit inhibition of a number of cytochrome P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes, but few studies have examined their inhibition of enzymes involved in nicotine metabolism. The goal of the present study was to...
Article
Introduction Cannabis is an increasingly popular recreational and medicinal drug in the USA. While cannabis is still a Schedule 1 drug federally, many states have lifted the ban on its use. With its increased usage, there is an increased potential for potential drug-drug interactions (DDI) that may occur with concomitant use of cannabis and pharmac...
Article
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Background: Nicotine metabolism is a major factor in nicotine dependence, with approximately 70-80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3'-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on...
Article
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Aim: 8-iso-prostaglandin F2α is a biomarker of lipid peroxidation, and one of the most commonly used measures of oxidative stress. It is an established biomarker of lung cancer risk. It is commonly measured by enzyme-linked immunosorbent assay. Given its importance, we developed a stable isotope dilution UPLC-tandem mass spectrometric method for t...
Article
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Exemestane (EXE) is an aromatase inhibitor used to treat hormone-dependent breast cancer. EXE is extensively metabolized, with unchanged EXE and its active metabolite 17-dihydroexemestane (17-DHE) accounting for 17 and 12%, respectively, of total plasma EXE in vivo The major circulating EXE metabolites are the cysteine conjugates of EXE and 17-DHE,...
Article
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To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rar...
Article
The 24th North American International Society for the Study of Xenobiotics (ISSX) meeting, held virtually from September 13 to 17, 2021, embraced the theme of "Broadening Our Horizons." This reinforces a key mission of ISSX: striving to share innovative science related to drug discovery and development. Session speakers and the ISSX New Investigato...
Article
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Exemestane (EXE) is used to treat post-menopausal women diagnosed with estrogen receptor positive (ER+) breast cancer. A major mode of metabolism of EXE and its active metabolite, 17β-dihydroexemestane (17β-DHE), is via glutathionylation by glutathione-S-transferase (GST) enzymes. The goal of the present study was to investigate the effects of gene...
Article
Opioids including morphine are mu-opioid receptor (MOR) agonists that suppress excitatory neurotransmitter release, hyperpolarize neuronal cells, and decrease overall excitability, resulting in the desired analgesic effect. As a result of their over-prescription, the still-growing opioid epidemic has devastated many communities, with many individua...
Article
Cannabis and cannabis-derived products are increasingly used for recreational and medical purposes including anxiety and epilepsy and are often concurrently used with other types of conventional medications. The concomitant use of cannabis with other therapeutic drugs has been shown to increase the likelihood of deleterious drug-drug interactions....
Article
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Introduction Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G×G) interactions that may influence the risk of non-small cell lung cancer (NSCLC). Methods Leveraging a total of 445,221 European-descent participants from the International Lung Cance...
Article
Polycyclic aromatic hydrocarbons (PAHs) and tobacco‐specific nitrosamines (TSNA) metabolism‐related genes play important role in the development of cancers. We assessed the associations of genetic variants in genes involved in the metabolism of PAHs and TSNA, and the risk of squamous cell carcinoma of the head and neck (SCCHN) in European populatio...
Preprint
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Background: Exemestane (EXE) is used to treat post-menopausal women diagnosed with estrogen receptor positive (ER+) breast cancer. A major mode of metabolism of EXE and its active metabolite, 17β-dihydroexemestane (17β-DHE), is via glutathionylation by glutathione-S-transferase (GST) enzymes. The goal of the present study was to investigate the eff...
Article
The major mode of metabolism of nicotine is via the formation of cotinine by the enzyme cytochrome P450 (CYP) 2A6. Cotinine undergoes further CYP2A6-mediated metabolism by hydroxylation to 3-hydroxycotinine and norcotinine but can also form cotinine-N-glucuronide and cotinine-N-oxide (COX). The goal of the present study was to investigate the enzym...
Article
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Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great succ...
Article
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Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim:...
Article
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Background: Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately...
Article
Objective To determine if a 2-day protocol measuring pharmacokinetic and pharmacodynamic characteristics can demonstrate drug-drug interactions when smoked cannabis is added to orally administered hydrocodone/acetaminophen combination products. Case Summary A 51-year-old non-Hispanic white male with chronic pain diagnoses participated in a 2-day p...
Article
Exemestane (EXE) is a hormonal therapy used to treat estrogen receptor positive (ER+) breast cancer by inhibiting the final step of estrogen biosynthesis catalyzed by the enzyme aromatase. Cysteine conjugates of EXE and its active metabolite 17β-dihydro-EXE (17β-DHE) are the major metabolites found in both the urine and plasma of patients taking EX...
Article
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The legalization of cannabis in many parts of the United States and other countries has led to a need for a more comprehensive understanding of cannabis constituents and their potential for drug-drug interactions. While (-)-trans-Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are the most abundant cannabinoids present in can...
Article
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The UDP-glucuronosyltransferase (UGT) family of enzymes play a central role in the metabolism and detoxification of a wide range of endogenous and exogenous compounds. UGTs exhibit a high degree of structural similarity and display overlapping substrate specificity, often making estimations of potential drug-drug interactions difficult to fully elu...
Article
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Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genome-wide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element, which activated hTERT transcription in a cell in a chromatin-dependent manner. VNTR2-1, consisti...
Article
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Significance Repetitive DNA sequences are abundant in the human genome, and their high variabilities contribute to genetic diversity and disease susceptibility. Here, we report that an intronic variable number tandem repeat element, VNTR2-1, is critical for the transcription of the human telomerase reverse transcriptase ( hTERT ) gene in a cell-con...
Preprint
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Introduction: Aberrant Wnt signalling, regulating cell development and stemness, is observed in many cancer entities. Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated to lung cancer susceptibility. Aim: To assess the asso...
Preprint
Full-text available
Background Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim To...
Preprint
Full-text available
There is growing evidence showing that sex disparity in lung cancer risk cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lun...
Article
Full-text available
Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of G...
Preprint
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Background: Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately...
Article
Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer...
Article
Introduction: Smoking remains a worldwide epidemic, and despite an increase in public acceptance of the harms of tobacco use, it remains the leading cause of preventable death. It is estimated that up to 70% of all smokers express a desire to quit, but only 3-5% of them are successful. Areas covered: The goal of this review was to evaluate the curr...
Article
The UDP-glycosyltransferase (UGT) family of enzymes are important in the metabolism of a variety of exogenous substances including polycyclic aromatic hydrocarbons (PAHs), a potent class of environmental carcinogens. As compared to the majority of UGT enzymes, which utilize UDP-glucuronic acid as a cosubstrate, UGT3A2 utilizes alternative cosubstra...
Preprint
Lung cancer is the leading cause of cancer death worldwide. Genome-wide association studies have revealed genetic risk factors, highlighting the role of smoking, family history, telomere regulation, and DNA damage-repair in lung cancer etiology. Many studies have focused on a single ethnic group to avoid confounding from variability in allele frequ...
Article
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PurposeTo examine associations between the UGT2B17 gene deletion and exemestane metabolites, and commonly reported side effects (fatigue, hot flashes, and joint pain) among postmenopausal women participating in the MAP.3 chemoprevention trial.Methods The analytical samples for the UGT2B17 analysis comprised 1752 women on exemestane and 1721 women o...
Article
Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-w...
Article
At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological...
Article
Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355...
Article
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Nicotine is the major pharmacologically active substance in tobacco. Several studies have examined genotypes related to nicotine metabolism, but few studies have been performed in the Mexican population. The objective was to identify associations between gene variants in metabolizing enzymes and the urinary levels of nicotine metabolites among Mexi...
Article
Alcohol is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk. Data from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 contr...
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Cellular stress response mechanisms normally function to enhance survival and allow for cells to return to homeostasis following an adverse event. Cancer cells often co-opt these same mechanisms as a means to evade apoptosis and mitigate a state of constant cellular stress. Activating transcription factor 5 (ATF5) is upregulated under diverse stres...
Article
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Bangladesh exhibits the second highest rate of smokeless tobacco (SLT) product usage in the world, and this has been associated with the high upper aerodigestive tract cancer incidence in this country. The goal of the present study was to examine the levels of the highly carcinogenic tobacco-specific nitrosamines (TSNAs) in Bangladeshi SLT products...
Article
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Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 ×...
Article
Background: A substantial proportion of cancer driver genes (CDGs) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. Methods: We selected expression-related single nucleotide polymorphisms (eSNPs) and nonsynonymous variants of...
Article
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The recent legalization of marijuana in many parts of the United States and other countries has led to an increased need for a more comprehensive understanding of the metabolism of marijuana constituents, specifically in regard to potential drug‐drug interactions (DDIs) with cannabinoids and their numerous metabolites. To understand the DDI potenti...
Article
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Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduc...
Article
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Polycyclic aromatic hydrocarbons (PAHs) are potent carcinogens and are a primary risk factor in the development of lung and other aerodigestive tract cancers in smokers. The detoxification of PAHs by glucuronidation is well-characterized for the UDP-glycosyltransferase (UGT) 1A, 2A, and 2B subfamilies; however, the role of the UGT3A subfamily in PA...
Article
Head and neck cancer (HNC) risk prediction models based on risk factor profiles have not yet been developed. We took advantage of the large database including 14 studies (1981-2010) in the US from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium to develop risk prediction models. Seventy percent of the data were used to deve...
Article
We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of this study has been to integrate the complete GWAS results with a large‐scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n=1,038) to identify candidate causal genes for lung cance...
Article
Background Recent reports have suggested that insulin vials purchased in community pharmacies do not meet the minimum required intact insulin concentration (≥95 U/mL) as defined by the United States Pharmacopeia. We sought to independently obtain multidose human insulin vials from a variety of community pharmacies across the state of Washington and...
Article
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During tobacco and e-cigarette use, nicotine is mainly metabolized in the human liver by CYP2A6. Given that a slower CYP2A6 metabolism has been associated with less vulnerability to develop nicotine dependence, the current studies sought to validate a novel CYP2A6 inhibitor, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), for its effect...
Article
Background: Tobacco use is a well-established risk factor for head and neck cancer (HNC). However, less is known about the potential impact of exposure to tobacco at an early age on HNC risk. Methods: We analyzed individual-level data on ever tobacco smokers from 27 case-control studies (17,146 HNC cases and 17,449 controls) in the International...
Article
Menthol, which creates mint flavor and scent, is often added to tobacco in both menthol and non-menthol cigarettes. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent tobacco carcinogen, is extensively metabolized to its equally carcinogenic metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) as (R)- or (S)-NNAL enantiomers....
Article
Genome‐wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies wit...
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The UDP-glucuronosyltransferase (UGT) family of enzymes are important in the metabolic elimination of a variety of endogenous compounds such as bile acids, steroids, and fat-soluble vitamins, as well as exogenous compounds including many pharmaceuticals. The UGT2B subfamily are the predominant isoforms expressed in human liver. The identification o...
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Tobacco specific nitrosamines (TSNAs) are among the most potent carcinogens found in cigarettes and smokeless tobacco products. Decreases in TSNA detoxification, particularly 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been associated with tobacco-related cancer incidence. NNK is metabolized by carbonyl reduction to its major carcino...
Article
Objectives: This study aimed at re-evaluating the strength and shape of the dose-response relationship between the combined (or joint) effect of intensity and duration of cigarette smoking and the risk of head and neck cancer (HNC). We explored this issue considering bivariate spline models, where smoking intensity and duration were treated as int...
Preprint
Full-text available
Impaired lung function is an indicator of obstructive pulmonary disease and may be a consequence of cigarette smoking, making it challenging to disentangle its role in lung cancer etiology. We investigated the shared genetic basis of pulmonary dysfunction and lung cancer susceptibility using genome-wide data from the UK Biobank (>370,000 individual...
Article
Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, se...
Conference Paper
ead and neck cancers are among the most common cancers in Southeast Asia and are likely to face sharp increases in the coming years due to the widespread use of smokeless tobacco (SLT) products. Bangladesh has the second highest oral cancer mortality rate as well as the second highest rate of SLT product usage worldwide. SLT products contain high l...
Article
The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterationsand tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses...
Article
Integrase strand transfer inhibitor (INSTI)-based regimens dominate initial human immunodeficiency virus treatment. Most INSTIs are metabolized predominantly via UDP-glucuronosyltransferases (UGTs). For drugs predominantly metabolized by UGTs, including INSTIs, in vitro data recovered from human liver microsomes (HLMs) alone often underpredict huma...
Article
Background: There is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders. Method...
Article
Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization anal...
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Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast...