Article
Toxicology
Reham Hassan, Daniela Gonzalez, Zaynab Hobloss, Lisa Brackhagen, Maiju Myllys, Adrian Friebel, Abdel-Latif Seddek, Rosemarie Marchan, Benedikt Cramer, Hans-Ulrich Humpf, Stefan Hoehme, Gisela H. Degen, Jan G. Hengstler, Ahmed Ghallab
Summary: The mycotoxin ochratoxin A (OTA) can cause liver and kidney damage, with the inhibition of CYP (cytochrome P450) by ABT exacerbating the toxicity of OTA. Urinary biomarkers of kidney damage KIM-1 and NGAL were significantly increased in mice treated with ABT and OTA, while blood biomarkers of liver damage ALT and AST were also significantly elevated in ABT pre-treated mice receiving OTA.
ARCHIVES OF TOXICOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Agnieszka Potega
Summary: The effectiveness of anticancer drugs is influenced by specific metabolites that can alter their therapeutic or toxic properties. One important process in metabolizing these drugs is conjugation with reduced glutathione, which can occur non-enzymatically or with the help of glutathione-dependent enzymes. Glutathione binds with anticancer drugs to form more polar and water-soluble glutathione S-conjugates, facilitating their excretion. This conjugation plays a role in detoxification, reducing the likelihood of the drugs reacting with cellular targets. However, some drugs become more active or toxic when transformed into thioethers through glutathione conjugation. Therefore, glutathione conjugation can also lead to pharmacological or toxicological effects through bioactivation reactions.
Article
Toxicology
Maria Estefania Gonzalez-Alvarez, Andrew Severin, Maryam Sayadi, Aileen F. Keating
Summary: PFOA exposure alters ovary weight and targets different proteins, potentially reducing female fecundity.
TOXICOLOGICAL SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Mohamed W. Attwa, Ali S. Abdelhameed, Nawaf A. Alsaif, Adnan A. Kadi, Haitham AlRabiah
Summary: PMB is the first targeted treatment for cholangiocarcinoma with good bioavailability and metabolic stability. A LC-MS/MS analytical method specific for PMB quantification was developed with high accuracy and precision.
Article
Chemistry, Medicinal
Lan Yang, Lihua Xin, Junzu Shi, Wei Li, Min Tian, Zixia Hu, Ying Peng, Jiang Zheng
Summary: Labetalol hydrochloride is commonly used for the treatment of hypertension and angina pectoris, but can cause adverse effects such as liver injury. The study found that SULTs may be involved in the metabolic activation of LHCl, and inhibiting SULTs could potentially mitigate hepatotoxicity associated with LHCl.
CHEMICAL RESEARCH IN TOXICOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Yoshinori Sato, Wenjing Dong, Tatsuro Nakamura, Naohiro Mizoguchi, Tasuku Nawaji, Miyu Nishikawa, Takenori Onaga, Shinichi Ikushiro, Makoto Kobayashi, Hiroki Teraoka
Summary: Metabolic activation is the main cause of chemical toxicity, including hepatotoxicity. This study aimed to identify the CYP2E homologue in zebrafish, a model organism used for toxicology and toxicity tests. By preparing transgenic zebrafish embryos/larvae expressing rat CYP2E1 and EGFP, the researchers confirmed the activity of rat CYP2E1 in the retina and liver of zebrafish and its involvement in APAP-induced toxicological endpoints.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biology
May R. Berenbaum, Daniel S. Bush, Ling-Hsiu Liao
Summary: Mycotoxins are secondary metabolites produced by filamentous fungi that can cause pathological responses in animal hosts or consumers. Insect herbivores can indirectly contribute to economically significant contamination by predisposing plants to infection by mycotoxin-producing phytopathogens. Some insect P450s have been identified to detoxify mycotoxins, which may play a role in developing biological remediation technologies and ensuring the safety of insects reared for human or livestock consumption.
CURRENT OPINION IN INSECT SCIENCE
(2021)
Article
Chemistry, Medicinal
Tyler B. Hughes, Noah Flynn, Na Le Dang, S. Joshua Swamidass
Summary: This study modeled four common metabolic transformations that lead to bioactivation and developed a bioactivation prediction model. The model accurately predicts metabolic pathways and distinguishes molecules that will undergo bioactivation reactions with a high degree of accuracy.
CHEMICAL RESEARCH IN TOXICOLOGY
(2021)
Article
Chemistry, Medicinal
Noah R. Flynn, S. Joshua Swamidass
Summary: Cytochrome P450 enzymes play a crucial role in drug metabolism, but can also generate reactive metabolites that may cause adverse reactions. In this study, a new model was developed using XenoNet 1.0 as a tool to generate metabolic networks and predict the authenticity of inferred Phase I metabolite structures. The model outperformed previous work and baselines, achieving high accuracy in separating observed and unobserved metabolites. The approach also proved robust in varying network contexts and showed potential for identifying new metabolites for experimental study.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Noah R. Flynn, S. Joshua Swamidass
Summary: Cytochrome P450 enzymes can eliminate small molecule drugs, but may produce reactive metabolites that react adversely with protein and DNA, leading to drug attrition or withdrawal. Previous models have helped understand how these enzymes modify molecule structure, but an integrative approach is needed to understand the network-level behavior of progenitor molecules. We developed a tool called XenoNet 1.0 that generates metabolic networks and extended it with a bidirectional message passing neural network. Our model significantly outperformed prior work and baselines, accurately predicting metabolite structures and important metabolic subnetworks.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Environmental Sciences
Yang Li, Meifang Li, Jian Liu, Guangning Nie, Hongyan Yang
Summary: This study investigated the effects of menopause on systems outside of the ovaries and the mechanisms of follicular loss using the VCD model. The results showed that rats treated with VCD exhibited irregular estrous cycles, a significant reduction in the number of primordial and preantral follicles, increased FSH levels and decreased AMH levels. Additionally, the total m6A level was significantly decreased after exposure to VCD. This study provides new insights into the mechanisms of follicle development in VCD-induced premature ovarian insufficiency.
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
(2023)
Article
Agriculture, Multidisciplinary
Ying Li, Changcheng Sun, Yutian Zhang, Xiang Chen, Haoyan Huang, Luyao Han, Han Xing, Di Zhao, Xijing Chen, Yongjie Zhang
Summary: This study aimed to investigate the metabolic profiles and species differences of the phase I metabolism of PTE and to explore subsequent detoxification after PTE bioactivation. PTE was found to be transformed into two pharmacologically active metabolites, pinostilbene and 3'-hydroxypterostilbene, with substantial species differences. Human CYP1A2 was mainly responsible for the demethylation and 3'-hydroxylation of PTE, while human glutathione S-transferase isoforms A2, T1, and A1 inactivated the ortho-quinone intermediate formed, indicating a potential protective pathway against PTE bioactivation-derived toxicity.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Wei Li, Zixia Hu, Chen Sun, Yuwei Wang, Weiwei Li, Ying Peng, Jiang Zheng
Summary: This study established a metabolic activation-based chemoproteomic platform to identify and locate protein adducts resulting from furan-containing compounds (FCCs) in liver cells. It successfully identified 171 lysine-based adducted proteins and 145 cysteine-based adducted proteins, which are mainly involved in ATP synthesis.
ACS CHEMICAL BIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Mary Alexandra Schleiff, Sasin Payakachat, Benjamin Mark Schleiff, S. Joshua Swamidass, Gunnar Boysen, Grover Paul Miller
Summary: The study identified a family of seven clinically relevant diphenylamine NSAIDs, which can be categorized into acetic acid and propionic acid subgroups with varying hepatotoxicity risks and bioactivation propensities. Structural modifications to the diphenylamine scaffold were found to influence the preference and efficiency of bioactivation pathways, leading to differences in metabolic reactions among the drugs.
Article
Biochemistry & Molecular Biology
Natalia Ortuzar, Kersti Karu, Daniela Presa, Goreti R. Morais, Helen M. Sheldrake, Steve D. Shnyder, Francis M. Barnieh, Paul M. Loadman, Laurence H. Patterson, Klaus Pors, Mark Searcey
Summary: This study examines the potential cytochrome P450 (CYP)-mediated cancer cell killing ability of seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors. Results demonstrate up to a 10-fold increase in bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Additionally, it is shown that CYP1A2, but not CYP1B1 or CYP3A4, has a propensity for potentiating these compounds, indicating a preference for CYP1A bioactivation.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)