Abstract:
:Drug induced liver injury (DILI) can require significant risk management in drug development and on occasion can cause morbidity or mortality, leading to drug attrition. Optimizing candidates preclinically can minimize hepatotoxicity risk, but it is difficult to predict due to multiple etiologies encompassing DILI, often with multifactorial and overlapping mechanisms. In addition to epidemiological risk factors, physicochemical properties, dose, disposition, lipophilicity, and hepatic metabolic function are also relevant for DILI risk. Better human-relevant, predictive models are required to improve hepatotoxicity risk assessment in drug discovery. Our hypothesis is that integrating mechanistically relevant hepatic safety assays with Bayesian machine learning will improve hepatic safety risk prediction. We present a quantitative and mechanistic risk assessment for candidate nomination using data from in vitro assays (hepatic spheroids, BSEP, mitochondrial toxicity, and bioactivation), together with physicochemical (cLogP) and exposure (Cmaxtotal) variables from a chemically diverse compound set (33 no/low-, 40 medium-, and 23 high-severity DILI compounds). The Bayesian model predicts the continuous underlying DILI severity and uses a data-driven prior distribution over the parameters to prevent overfitting. The model quantifies the probability that a compound falls into either no/low-, medium-, or high-severity categories, with a balanced accuracy of 63% on held-out samples, and a continuous prediction of DILI severity along with uncertainty in the prediction. For a binary yes/no DILI prediction, the model has a balanced accuracy of 86%, a sensitivity of 87%, a specificity of 85%, a positive predictive value of 92%, and a negative predictive value of 78%. Combining physiologically relevant assays, improved alignment with FDA recommendations, and optimal statistical integration of assay data leads to improved DILI risk prediction.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Williams DP,Lazic SE,Foster AJ,Semenova E,Morgan Pdoi
10.1021/acs.chemrestox.9b00264subject
Has Abstractpub_date
2020-01-21 00:00:00pages
239-248issue
1eissn
0893-228Xissn
1520-5010journal_volume
33pub_type
杂志文章abstract::Exposure to arsenic affects large human populations worldwide and has been associated with a long list of human diseases, including skin, bladder, lung, and liver cancers, diabetes, and cardiovascular disorders. In addition, there are large individual differences in susceptibility to arsenic-induced diseases, which ar...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx4002868
更新日期:2013-12-16 00:00:00
abstract::Organochlorine (OC) compounds are some of the main toxicants present in the food web and target several cellular systems including the nonspecific immune system. The objective of this study was to test the hypothesis that OC compounds that activate neutrophils share common structural features. Using activation of phos...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0155449
更新日期:2002-02-01 00:00:00
abstract::Atrazine (ATR) is extensively used worldwide as an herbicide, with a global ecological influence. The widespread distribution of herbicides may be one of the possible reasons for the decline in the global amphibian population. The acute toxicity and potential toxicological mechanisms of ATR on the immune system of fro...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00238
更新日期:2015-10-19 00:00:00
abstract::beta-Carotene and other carotenoids are thought to exert disease preventive actions by scavenging reactive free radicals, but the mechanisms of these reactions are poorly understood. We detected products formed by reaction of beta-carotene with alkoxyl, and alkylperoxyl free radicals generated by thermolysis of azobis...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx950151t
更新日期:1996-01-01 00:00:00
abstract::The Adverse Outcome Pathway (AOP) paradigm details the existing knowledge that links the initial interaction between a chemical and a biological system, termed the molecular initiating event (MIE), through a series of intermediate events, to an adverse effect. An important example of a well-defined MIE is the formatio...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.6b00099
更新日期:2016-06-20 00:00:00
abstract::Iron in iron overload disease is present as non-transferrin-bound iron, consisting of iron, citrate, and albumin. We investigated the redox properties of iron citrate by electrochemistry, by the kinetics of its reaction with ascorbate, by ESR, and by analyzing the products of reactions of ascorbate with iron citrate c...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500377b
更新日期:2015-04-20 00:00:00
abstract::A freely available Windows-based program, RNSim1A, is utilized to predict metal-independent reactive nitrogen species (RNS) chemistry (oxidation, nitrosation, and nitration) under simulated biological conditions and make the following specific predictions. (1) The peak in oxidative reactions that occurs in vitro with ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx060061w
更新日期:2006-09-01 00:00:00
abstract::The clinical use of the immunosuppressant calcineurin inhibitor cyclosporine is limited by its nephrotoxicity. This is enhanced when combined with the immunosuppressive mTOR inhibitor sirolimus. Nephrotoxicity of both drugs is not yet fully understood. The goal was to gain more detailed mechanistic insights into the t...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800253x
更新日期:2009-01-01 00:00:00
abstract::Ochratoxin A (OTA) is a mycotoxin that shows potent nephrotoxicity and renal carcinogenicity in rodents. One hypothesis for OTA-induced tumor formation is based on its genotoxic properties that are promoted by oxidative metabolism. Like other chlorinated phenols, OTA undergoes an oxidative dechlorination process to ge...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx060138g
更新日期:2006-09-01 00:00:00
abstract::Aflatoxin Q1 8,9-oxide was synthesized and found to yield lower levels of N7-guanyl adducts than obtained from aflatoxin B1 8,9-oxide when mixed with calf thymus DNA or Salmonella typhimurium TA 98 cells. However, when S. typhimurium TA 98 was treated with the (analogous) epoxides of aflatoxin B1, aflatoxin G1, aflato...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00026a009
更新日期:1992-03-01 00:00:00
abstract::2,3-dimethoxy-1,4-naphthoquinone (CAS-RN 6959-96-3) (DMNQ) and 2-methyl-1,4-naphthoquinone (CAS-RN 58-27-5) (MNQ:menadione) are effective one electron redox cycling chemicals in vitro. In addition, in vitro MNQ forms a thioether conjugate with glutathione by nucleophilic attack at the third carbon. In contrast, here w...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800472z
更新日期:2009-04-01 00:00:00
abstract::Nevirapine (NVP) treatment is associated with a significant incidence of skin rash in humans, and it also causes a similar immune-mediated skin rash in Brown Norway (BN) rats. We have shown that the sulfate of a major oxidative metabolite, 12-OH-NVP, covalently binds in the skin. The fact that the sulfate metabolite i...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400098z
更新日期:2013-05-20 00:00:00
abstract::The recent guidance on "Safety Testing of Drug Metabolites" issued by the U.S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER) has highlighted the importance of identifying and characterizing drug metabolites as early as possible in drug discovery and development. Furthermore, upon identif...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx8003328
更新日期:2009-02-01 00:00:00
abstract::Free-radical oxidation of human plasma low-density lipoprotein (LDL) produces (carboxyalkyl)pyrrole (CAP) epitopes that were detected with enzyme-linked immunosorbent assays using antibodies raised against keyhole limpet hemocyanin (KLH)-bound 2-(omega-carboxyheptyl)-pyrrole (CHP) and 2-(omega-carboxypropyl)pyrrole (C...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx970112c
更新日期:1997-12-01 00:00:00
abstract::The effect of adduct stereochemistry on the susceptibility to hydrolysis by snake venom (VPD) and bovine spleen (SPD) phosphodiesterases was investigated with short deoxyoligonucleotides containing defined adducts derived from alkylation of the exocyclic 6-amino group of dA by polycyclic aromatic hydrocarbon diol epox...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx010092l
更新日期:2001-09-01 00:00:00
abstract::The reaction of the alpha, beta-unsaturated ketones methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) with nucleosides and 5'-mononucleotides was studied. The genotoxic activity of MVK and EVK in the SOS Chromotest was investigated. Three different types of adducts with deoxyguanosine were found and their structu...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00019a007
更新日期:1991-01-01 00:00:00
abstract::Butadiene monoxide, a toxic metabolite of 1,3-butadiene, is a substrate for the human placental glutathione (GSH) S-transferase. The products have been identified as S-(2-hydroxy-3-buten-1-yl)glutathione (I) and S-(1-hydroxy-3-buten-2-yl)glutathione (II). S-(4-hydroxy-2-buten-1-yl)glutathione (III), which was formed c...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00022a006
更新日期:1991-07-01 00:00:00
abstract::Because the manganese-based contrast agents used in magnetic, resonance imaging are unstable in vivo, some concern exists about the potential toxicity coming from the Mn2+ released by the complexes. This potential problem arises because the manganese is known to accumulate in the brain of people intoxicated by this me...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960194p
更新日期:1997-04-01 00:00:00
abstract::Topoisomerase II regulates DNA topology by generating transient double-stranded breaks. The anticancer drug etoposide targets topoisomerase II and is associated with the formation of secondary leukemias in patients. The quinone and catechol metabolites of etoposide may contribute to strand breaks that trigger leukemic...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400205n
更新日期:2013-08-19 00:00:00
abstract::Lumiracoxib (Prexige; 2-[(2-fluoro-6-chlorophenyl)amino]-5-methyl-benzeneacetic acid) is a cyclooxygenase-2 selective inhibitor for the symptomatic treatment of osteoarthritis. Recently, the drug has been withdrawn in several countries due to serious liver side effects. Li et al. recently have shown that lumiracoxib i...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx8002356
更新日期:2009-01-01 00:00:00
abstract::Enzyme-linked immunosorbent assays (ELISAs) are reported for the detection of atrazine and its principle metabolite in human urine. The ELISAs can be used with crude urine or following extraction and partial purification by methods described in this report. GC, MS, and HPLC techniques were used to confirm and compleme...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00031a017
更新日期:1993-01-01 00:00:00
abstract::Many herbal medicines such as epimedium have been reported to cause adverse effects, and icaritin is the common aglycone of many glucosides in epimedium. Our present work aimed at the clarification of the metabolic activation of icaritin possibly responsible for the adverse effects of epimedium. A quinone methide meta...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00418
更新日期:2019-06-17 00:00:00
abstract::The growth-promoting effects of estrogens in hormone-dependent tumor tissues involve receptor-mediated pathways that are well-recognized; however, the role of estrogens in tumor initiation remains controversial. Estrogen metabolites, primarily the catechol estrogens (CE's), have been implicated in tumor initiation via...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx980128i
更新日期:1999-03-01 00:00:00
abstract::The N-reduction of the centrally acting alpha 2-adrenoreceptor agonist guanoxabenz (Benzérial), an N-hydroxyamidinohydrazone, to the amidinohydrazone guanabenz (Wytensin, Hipten, Rexitene) by microsomal fractions from rabbits, pigs and humans has been detected in vitro. The conversion rates with rabbit microsomal frac...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx9502047
更新日期:1996-06-01 00:00:00
abstract::Caffeine on alkaline hydrolysis produces caffeidine [1-methyl-4-(methylamino)-5-(N-methylcarbamoyl)imidazole] and caffeidine acid [N-[4-(5-carboxy-1-methylimidazolyl)]-N,N'-dimethylurea]. We now report the synthesis and chemical characterization of mononitrosocaffeidine [1-methyl-4-(N-methyl-N-nitrosoamino)-5-(N-methy...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00031a008
更新日期:1993-01-01 00:00:00
abstract::The use of powerful analytical technologies to detect endogenous carbonyls formed as byproducts of oxidative cell injury has revealed that these species contribute to many human diseases. As electrophiles, they are attacked by reactive centers in cell macromolecules to form adducts, the levels of which serve as useful...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx700399q
更新日期:2008-04-01 00:00:00
abstract::The need for large-scale direct synthesis of stereochemically defined and site-specific benzo[alpha]pyrenediol epoxide-oligodeoxyribonucleotide adducts for detailed NMR and other biochemical and physicochemical studies has necessitated a better understanding of variables that lead to an enhancement of the reaction yie...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx980006q
更新日期:1998-04-01 00:00:00
abstract::The diarrhetic shellfish toxin composition in the digestive glands of mussels from the northern Adriatic sea was investigated. Along with known yessotoxins, identified by comparison of their chromatographic and spectral properties with those reported in the literature, we isolated a new analogue of yessotoxin, 42,43,4...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx000259v
更新日期:2001-05-01 00:00:00
abstract::To obtain definitive information about the mechanisms of urinary calculus formation and the structural characteristics of the calculi induced by biphenyl administration in rats, with a focus on the sex dependency, the constituents of the urinary calculi were analyzed by HPLC, inductively coupled plasma spectroscopy (I...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0000163
更新日期:2000-08-01 00:00:00
abstract::Quinones represent a class of toxicological intermediates which can create a variety of hazardous effects in vivo, including acute cytotoxicity, immunotoxicity, and carcinogenesis. The mechanisms by which quinones cause these effects can be quite complex. Quinones are Michael acceptors, and cellular damage can occur t...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx9902082
更新日期:2000-03-01 00:00:00