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Introduction
Grover P Miller currently works at the Department of Biochemistry and Molecular Biology , University of Arkansas for Medical Sciences. The goals of his research are to assess and interpret the biological significance of metabolic activation and clearance of molecules especially in relation to pharmacological and toxicological effects on humans. In practice, his group develops and leverages powerful analytical and biochemical tools to identify and quantitate small molecules including drugs, pollutants, and food additives as they undergo transformations through metabolic pathways. They then correlate those findings to biological activity and in vivo outcomes.
Additional affiliations
June 1992 - December 1997
August 1988 - May 1992
January 1997 - July 2001
Publications
Publications (114)
Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive me...
This annual review is the eighth of its kind since 2016 (Baillie et al. 2016, Khojasteh et al. 2017, Khojasteh et al. 2018, Khojasteh et al. 2019, Khojasteh et al. 2020, Khojasteh et al. 2021, Khojasteh et al. 2022). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation.
With the 50th year mark since the launch of Drug Metabolism and Disposition journal, the field of drug metabolism and bioactivation has advanced exponentially in the past decades (Guengerich 2023).This has, in a major part, been due to the continued advances across the whole spectrum of applied technologies in hardware, software, machine learning (...
Tyrosine kinase inhibitors (TKIs) are increasingly popular drugs used to treat more than a dozen different diseases including some forms of cancer. Despite having fewer adverse effects than traditional chemotherapies, they are not without risks. Liver injury is a particular concern. Of the FDA-approved TKIs, approximately 40% cause hepatotoxicity....
In 2019, synthetic cannabinoids accounted for more than one-third of new drugs of abuse worldwide; however, assessment of associated health risks is not ethical for controlled and often illegal substances, making CD-1 mouse exposure studies the gold standard. Interpretation of those findings then depends on the similarity of mouse and human metabol...
This year’s review on bioactivation and reactivity began as a part of the annual review on biotransformation and bioactivation led by Cyrus Khojasteh (see references). Increased contributions from experts in the field led to the development of a stand alone edition for the first time this year focused specifically on bioactivation and reactivity. O...
Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend...
Diphenylamine NSAIDs are taken frequently for chronic pain conditions, yet their use may potentiate hepatotoxicity risks through poorly characterized metabolic mechanisms. Our previous work revealed that seven marketed or withdrawn diphenylamine NSAIDs undergo bioactivation into quinone-species metabolites, whose reaction specificities depended on...
Drug-drug interactions account for up to 30% of adverse drug reactions. Increasing prevalence of electronic health records (EHRs) offers a unique opportunity to build machine learning algorithms to identify drug-drug interactions that drive adverse events. In this study, we investigated hospitalizations’ data to study drug interactions with non-ste...
The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, and biomolecul...
Diphenylamine NSAIDs are highly prescribed therapeutics for chronic pain despite causing symptomatic hepatotoxicity through mitochondrial damage in five percent of patients taking them. Differences in toxicity are attributed to structural modifications to the diphenylamine scaffold rather than its inherent toxicity. We hypothesize that marketed dip...
This annual review is the sixth of its kind since 2016 (see references). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation and bioactivation. These fields are constantly evolving with new molecular structures and discoveries of corresponding pathways for metabolism that impact...
Meloxicam is a thiazole-containing NSAID that was approved for marketing with favorable clinical outcomes despite being structurally similar to the hepatotoxic sudoxicam. Introduction of a single methyl group on the thiazole results in an overall lower toxic risk, yet the group’s impact on P450 isozyme bioactivation is unclear. Through analytical m...
Meclofenamate is a nonsteroidal anti-inflammatory drug used in the treatment of mild-to-moderate pain yet poses a rare risk of hepatotoxicity through an unknown mechanism. Nonsteroidal anti-inflammatory drug (NSAID) bioactivation is a common molecular initiating event for hepatotoxicity. Thus, we hypothesized a similar mechanism for meclofenamate a...
In 2020, nearly one-third of new drugs on the global market were synthetic cannabinoids including the drug of abuse N-(1-adamantyl)-1-(5-pentyl)-1H-indazole-3-carboxamide (5F-APINACA, 5F-AKB48). Knowledge of 5F-APINACA metabolism provides a critical mechanistic basis to interpret and predict abuser outcomes. Prior qualitative studies identified whi...
Developing a Faculty Retention Plan for an Academic Medical Center in a Small Rural State
Biotransformation is one of the main mechanisms used by the body to eliminate drugs. As drug molecules become more complicated, the involvement of drug metabolizing enzymes increases beyond those that are typically studied, such as the cytochrome P450 enzymes. In this review, we try to capture the many outstanding articles that were published in th...
Terbinafine N-dealkylation pathways result in formation of 6,6-dimethyl-2-hepten-4-ynal (TBF-A), a reactive allylic aldehyde, that may initiate idiosyncratic drug induced liver toxicity. Previously, we reported on the importance of CYP2C19 and 3A4 as major contributors to TBF-A formation. In this study, we expanded on those efforts to assess indivi...
Pediatric patients are at elevated risk of adverse drug reactions, and there is insufficient information on drug safety in children. Complicating risk assessment in children, there are numerous age-dependent changes in the absorption, distribution, metabolism, and elimination of drugs. A key contributor to age-dependent drug toxicity risk is the on...
In the past three decades, ADME sciences have become an integral component of the drug discovery and development process. At the same time, the field has continued to evolve, thus, requiring ADME scientists to be knowledgeable of and engage with diverse aspects of drug assessment: from pharmacology to toxicology, and from in silico modeling to in v...
This article has been withdrawn by Samuel Freyaldenhoven, Yicong Li, Arif M. Kocabas, Grover P. Miller, and Fusun Kilic. Despite attempts, Enrit Ziu, Serra Ucer, and Raman Ramanagoudr-Bhojappa could not be reached for conference on this decision. Dr. Kilic contacted the editorial office to report errors in Fig. 3A and Fig 8 of their article. The Jo...
Adverse drug reactions (ADRs) are dangerous and expensive. Idiosyncratic ADRs, especially the difficult to predict, rare and severe hypersensitivity‐driven ADRs, are the leading cause of medicine withdrawal and termination of clinical development. At the same time, a large proportion of drugs are not associated with hypersensitivity driven ADRs, of...
Lamisil (terbinafine) may cause idiosyncratic liver toxicity through a proposed toxicological mechanism involving the reactive metabolite 6,6-dimethyl-2-hepten-4-ynal (TBF-A). TBF-A toxicological relevance remains unclear due to a lack of identification of pathways leading to and competing with TBF-A formation. We resolved this knowledge gap by com...
: For this pilot study, we leveraged metabolite patterns for warfarin patients to more accurately assess clinically relevant differences in drug metabolism. We tested our hypothesis that plasma metabolite levels correlate with the influence of clinical factors on R-warfarin and S-warfarin metabolism (warfarin metabolic phenotype). We recruited 29 p...
This annual review is the third one to highlight recent advances in the study and assessment of biotransformations and bioactivations (Table 1). We followed the same format as the previous years with selection and authoring each section (see Baillie et al. 2016 Baillie TA, Dalvie D, Rietjens IMCM, Cyrus Khojasteh S. 2016. Biotransformation and bioa...
• Coumadin (R/S-warfarin) metabolism plays a critical role in patient response to anticoagulant therapy. Several cytochrome P450s oxidize warfarin into R/S-6-, 7-, 8-, 10, and 4′-hydroxywarfarin that can undergo subsequent glucuronidation by UDP-glucuronosyltransferases (UGTs); however, current studies on recombinant UGTs cannot be adequately extra...
Cytochromes P450 (CYPs) oxidize alkylated amines commonly found in drugs and other biologically active molecules, splitting them into an amine and an aldehyde. Metabolic studies usually neglect to report or investigate aldehydes, even though they can be toxic. It is assumed that they are efficiently detoxified into carboxylic acids and alcohols. Ne...
Most small-molecule drug candidates fail before entering the market, frequently because of unexpected toxicity. Often, toxicity is detected only late in drug development, because many types of toxicities, especially idiosyncratic adverse drug reactions (IADRs), are particularly hard to predict and detect. Moreover, drug-induced liver injury (DILI)...
Coumadin (rac-warfarin) is the most commonly used anticoagulant in the world, yet its clinical use is often challenging due to a narrow therapeutic range and inter-individual variations in response. A critical contributor to the uncertainty is variability in warfarin metabolism, which includes mostly oxidative but also reductive pathways. Reduction...
Cytochrome P450 2E1 (CYP2E1) metabolizes an extensive array of pollutants, drugs, and other small molecules, often resulting in bioactivation to reactive metabolites. Therefore, it is unsurprising that it has been the subject of decades of research publications and reviews. However, while CYP2E1 has historically been studied in the endoplasmic reti...
We are pleased to present a second annual issue highlighting a previous year’s literature on biotransformation and bioactivation. Each contributor to this issue worked independently to review the articles published in 2016 and proposed three to four articles, which he or she believed would be of interest to the broader research community. In each s...
Structural alerts are commonly used in drug discovery to identify molecules likely to form reactive metabolites, and thereby become toxic. Unfortunately, as useful as structural alerts are, they do not effectively model if, when, and why metabolism renders safe molecules toxic. Toxicity due to a specific structural alert is highly conditional, depe...
Cytochrome P450 2E1 (CYP2E1) metabolizes low molecular weight hydrophobic compounds, including 1,3-butadiene, which is converted by CYP2E1 to electrophilic epoxide metabolites that covalently modify cellular proteins and DNA. Previous CYP2E1 studies have mainly focused on the enzyme localized in the endoplasmic reticulum (erCYP2E1); however, active...
Glioblastoma multiforme (GBM) is the most malignant primary brain tumor and has a median survival time of 12 months, due in large part to poor responses to chemo‐ and radio‐therapy. These tumors exhibit high levels of DNA damage response activation before treatment and this likely plays a role in the inherent chemo‐ and radio‐resistance of GBM. Y‐f...
Over-expression of the translesion synthesis polymerase (TLS pol) hpol κ in glioblastomas has been linked to a poor patient prognosis; however, the mechanism promoting higher expression in these tumors remains unknown. We determined that activation of the aryl hydrocarbon receptor (AhR) pathway in glioblastoma cells leads to increased hpol κ mRNA a...
Cytochrome P450 2E1 (CYP2E1) detoxifies or bioactivates many low molecular-weight compounds. Most knowledge about CYP2E1 activity relies on studies of the enzyme localized to endoplasmic reticulum (erCYP2E1); however, CYP2E1 undergoes transport to mitochondria (mtCYP2E1) and becomes metabolically active. We report the first comparison of in vitro s...
Risk assessment for exposure to mixtures of drugs and pollutants relies heavily on in vitro characterization of their bioactivation and/or metabolism individually and extrapolation to mixtures assuming no interaction. Herein, we demonstrated that in vitro CYP2E1 metabolic activation of acetaminophen and styrene mixtures could not be explained throu...
Drug toxicity is frequently caused by electrophilic reactive metabolites that covalently bind to proteins. Epoxides comprise a large class of three-membered cyclic ethers. These molecules are electrophilic and typically highly reactive due to ring tension and polarized carbon-oxygen bonds. Epoxides are metabolites often formed by cytochromes P450 a...
Coumadin (R/S‐warfarin) anticoagulation therapy remains challenging due to a narrow therapeutic range and high inter‐individual variations in response. We hypothesize that plasma metabolite profiles capture clinically relevant variations in warfarin metabolism as a resource to improve therapeutic strategies to minimize risk. We profiled R‐ and S‐wa...
Drug toxicity is often caused by electrophilic reactive metabolites that covalently bind to proteins. Consequently, the quantitative strength of a molecule's reactivity with glutathione (GSH) is a frequently used indicator of its toxicity. Through cysteine, GSH (and proteins) scavenges reactive molecules to form conjugates in the body. GSH conjugat...
CYP2E1 metabolizes a wide array of small, hydrophobic molecules, resulting in their detoxification or activation into carcinogens through Michaelis-Menten as well as cooperative mechanisms. Nevertheless, the molecular determinants for CYP2E1 specificity and metabolic efficiency toward these compounds are still unknown. Herein, we employed computati...
The widely used anticoagulant Coumadin (R/S-warfarin) undergoes oxidation by cytochromes P450 into hydroxywarfarins that subsequently become conjugated for excretion in urine. Hydroxywarfarins may modulate warfarin metabolism transcriptionally or through direct inhibition of cytochromes P450 and thus, UGT action toward hydroxywarfarin elimination m...
CYP2E1 has been implicated in the bioactivation of many small molecules into reactive metabolites which form adducts with proteins and DNA, and thus a better understanding of the molecular determinants of its selectivity are critical for accurate toxicological predictions. In this study, we determined the potency of inhibition of human CYP2E1 for v...
CYP2E1 plays a role in the metabolic activation and elimination of aniline, yet there are conflicting reports on its mechanism of action, and hence relevance, in aniline metabolism. Based on our work with similar compounds, we hypothesized that aniline binds two CYP2E1 sites during metabolism resulting in cooperative reaction kinetics and tested th...
CYP2E1 metabolizes 1,3-butadiene (BD) into genotoxic and possibly carcinogenic 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-epoxy-3,4-butanediol (EB-diol). The dose response of DNA and protein adducts derived from BD metabolites increase linearly at low BD exposures and then saturate at higher exposures in rats, but not mice. It wa...
CYP2E1 plays a critical role in detoxication and carcinogenic activation of drugs, pollutants, and dietary compounds; however, these metabolic processes can involve poorly characterized cooperative interactions that compromise the ability to understand and predict CYP2E1 metabolism. Herein, we employed an array of ten azoles with an emphasis on pyr...
The present invention encompasses classical cannabinoid metabolites and uses thereof.
Coumadin (R/S-warfarin) is a commonly prescribed anticoagulant for over ∼20 million Americans. Although highly efficacious, positive clinical outcomes during warfarin therapy depend on maintaining a narrow therapeutic range for the drug. This goal is challenging due to large inter-individual variability in patient response, which has been attribute...
Abstract 1. Cooperative interactions are frequently observed in the metabolism of drugs and pollutants by cytochrome P450s; nevertheless, the molecular determinants for cooperativity remain elusive. Previously, we demonstrated that steady-state styrene metabolism by CYP2E1 exhibits positive cooperativity. 2. We hypothesized that styrene metabolites...
Coumadin (R/S-warfarin) is a highly efficacious and widely used anticoagulant; however, its highly variable metabolism remains an important contributor to uncertainties in therapeutic responses. Pharmacogenetic studies report conflicting findings on the clinical relevance of CYP2C19. A resolution to this controversy is impeded by a lack of detail o...
We are the first to report allosterism during styrene oxidation by recombinant CYP2E1 and human liver microsomes. At low styrene concentrations, oxidation is inefficient because of weak binding to CYP2E1 (K(s) = 830 μM). A second styrene molecule then binds CYP2E1 with higher affinity (K(ss) = 110 μM) and significantly improves oxidation to achieve...
In heterologous and endogenous expression systems, we studied the role of ERp44 and its complex partner endoplasmic reticulum (ER) oxidase 1-α (Ero1-Lα) in mechanisms regulating disulfide bond formation for serotonin transporter (SERT), an oligomeric glycoprotein. ERp44 is an ER lumenal chaperone protein that favors the maturation of disulfide-link...
Introduction:
Coumadin (R/S-warfarin) is the most widely prescribed oral anticoagulant in the world; nevertheless, its clinical use is complicated by unpredictability in dose requirements to achieve and maintain optimal anticoagulation. Variations in warfarin metabolism among patients contribute to unpredictability in therapeutic responses. Studyi...
Effective Coumadin (R/S-warfarin) therapy is complicated by inter-individual variability in metabolism. Recent studies have demonstrated that CYP3A isoforms likely contribute to patient responses and clinical outcomes. Despite a significant focus on CYP3A4, little is known about CYP3A5 and CYP3A7 metabolism of warfarin. Based on our studies, recomb...
Effective coumadin (R/S-warfarin) therapy is complicated by inter-individual variability in metabolism. Recent studies have demonstrated that CYP3A isoforms likely contribute to patient responses and clinical outcomes. Despite a significant focus on CYP3A4, little is known about CYP3A5 and CYP3A7 metabolism of warfarin. Based on our studies, recomb...
See also Rulcova A, Prokopova I, Krausova L, Bitman M, Vrzal R, Dvorak Z, Blahos J, Pavek P. Stereoselective interactions of warfarin enantiomers with the pregnane X nuclear receptor in gene regulation of major drug-metabolizing cytochrome P450 enzymes. This issue, pp 2708–17.
Coumadin (R/S-warfarin) anticoagulant therapy poses a risk to over 50 million Americans, in part due to interpersonal variation in drug metabolism. Consequently, it is important to understand how metabolic capacity is influenced among patients. Cytochrome P450s (P450 or CYP for a specific isoform) catalyze the first major step in warfarin metabolis...
The widely prescribed anticoagulant, Coumadin (racemic R/S-warfarin), Bristol-Myers Squibb Company, Clinton, NY has a narrow therapeutic range and wide interindividual response due, in part, to drug metabolism. Early identification of hydroxywarfarins (OHWARs), especially S-7-OHWAR, as major metabolites fostered studies characterizing cytochrome P4...
As a promiscuous redox partner, the biological role of cytochrome P450 reductase (CPR) depends significantly on protein-protein interactions. We tested a hypothesized CPR docking site by mutating D113, E115, and E116 to alanine and assaying activity toward various electron acceptors as a function of ionic strength. Steady-state cytochrome c studies...
Coumadin (R-, S-Warfarin [War]) is a challenging drug to accurately dose, both initiallyand for maintenance, because of its narrow therapeutic range andwide inter-patient variability. Another challenge in this therapy is that Coumadin is typically administered as a racemic mixture. The R and S enantiomers are oxidized by multiple hepatic CYPs at 5...