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β-内酰胺治疗芬太尼过量小鼠模型中的肝脏代谢组学和炎症谱

Liver Metabolomics and Inflammatory Profiles in Mouse Model of Fentanyl Overdose Treated with Beta-Lactams.

作者信息

Alasmari Fawaz, Alasmari Mohammed S, Assiri Mohammed A, Alswayyed Mohammed, Rizwan Ahamad Syed, Alhumaydhi Abdulrahman I, Arif Bandar I, Aljumayi Sahar R, AlAsmari Abdullah F, Ali Nemat, Childers Wayne E, Abou-Gharbia Magid, Sari Youssef

机构信息

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.

出版信息

Metabolites. 2023 Aug 21;13(8):965. doi: 10.3390/metabo13080965.

DOI:10.3390/metabo13080965
PMID:37623908
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10456707/
Abstract

Fentanyl is a highly potent opioid analgesic that is approved medically to treat acute and chronic pain. There is a high potential for overdose-induced organ toxicities, including liver toxicity, and this might be due to the increase of recreational use of opioids. Several preclinical studies have demonstrated the efficacy of beta-lactams in modulating the expression of glutamate transporter-1 (GLT-1) in different body organs, including the liver. The upregulation of GLT-1 by beta-lactams is associated with the attenuation of hyperglutamatergic state, which is a characteristic feature of opioid use disorders. A novel experimental beta-lactam compound with no antimicrobial properties, MC-100093, has been developed to attenuate dysregulation of glutamate transport, in part by normalizing GLT-1 expression. A previous study showed that MC-100093 modulated hepatic GLT-1 expression with subsequent attenuation of alcohol-increased fat droplet content in the liver. In this study, we investigated the effects of fentanyl overdose on liver metabolites, and determined the effects of MC-100093 and ceftriaxone in the liver of a fentanyl overdose mouse model. Liver samples from control, fentanyl overdose, and fentanyl overdose ceftriaxone- or MC-100093-treated mice were analyzed for metabolomics using gas chromatography-mass spectrometry. Heatmap analysis revealed that both MC-100093 and ceftriaxone attenuated the effects of fentanyl overdose on several metabolites, and MC-100093 showed superior effects. Statistical analysis showed that MC-100093 reversed the effects of fentanyl overdose in some metabolites. Moreover, enrichment analysis revealed that the altered metabolites were strongly linked to the glucose-alanine cycle, the Warburg effect, gluconeogenesis, glutamate metabolism, lactose degradation, and ketone body metabolism. The changes in liver metabolites induced by fentanyl overdose were associated with liver inflammation, an effect attenuated with ceftriaxone pre-treatments. Ceftriaxone normalized fentanyl-overdose-induced changes in liver interleukin-6 and cytochrome CYP3A11 (mouse homolog of human CYP3A4) expression. Our data indicate that fentanyl overdose impaired liver metabolites, and MC-100093 restored certain metabolites.

摘要

芬太尼是一种强效阿片类镇痛药，已获医学批准用于治疗急性和慢性疼痛。过量使用芬太尼导致器官毒性的可能性很高，包括肝毒性，这可能是由于阿片类药物娱乐性使用增加所致。多项临床前研究已证明β-内酰胺类药物在调节包括肝脏在内的不同身体器官中谷氨酸转运体-1（GLT-1）表达方面的功效。β-内酰胺类药物对GLT-1的上调与高谷氨酸能状态的减轻有关，而高谷氨酸能状态是阿片类药物使用障碍的一个特征。一种新型的无抗菌特性的实验性β-内酰胺化合物MC-100093已被开发出来，以部分通过使GLT-1表达正常化来减轻谷氨酸转运失调。先前的一项研究表明，MC-100093调节肝脏GLT-1表达，随后减轻肝脏中酒精增加的脂肪滴含量。在本研究中，我们研究了芬太尼过量对肝脏代谢物的影响，并确定了MC-100093和头孢曲松在芬太尼过量小鼠模型肝脏中的作用。使用气相色谱-质谱联用仪对来自对照、芬太尼过量以及经头孢曲松或MC-100093治疗的芬太尼过量小鼠的肝脏样本进行代谢组学分析。热图分析显示，MC-100093和头孢曲松均减轻了芬太尼过量对几种代谢物的影响，且MC-100093显示出更好的效果。统计分析表明，MC-100093逆转了芬太尼过量对某些代谢物的影响。此外，富集分析显示，改变的代谢物与葡萄糖-丙氨酸循环、瓦伯格效应、糖异生、谷氨酸代谢、乳糖降解和酮体代谢密切相关。芬太尼过量引起的肝脏代谢物变化与肝脏炎症有关，头孢曲松预处理可减轻这种影响。头孢曲松使芬太尼过量引起的肝脏白细胞介素-6和细胞色素CYP3A11（人CYP3A4的小鼠同源物）表达变化正常化。我们的数据表明，芬太尼过量损害肝脏代谢物，而MC-100093可恢复某些代谢物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/6be2a0faaecf/metabolites-13-00965-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/d5594efa7325/metabolites-13-00965-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/5a0fa7af4bad/metabolites-13-00965-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/14346e71febd/metabolites-13-00965-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/6be2a0faaecf/metabolites-13-00965-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/d5594efa7325/metabolites-13-00965-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/0a3ac9ab98bc/metabolites-13-00965-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/f1bd902cee7f/metabolites-13-00965-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/08b82cefa5ec/metabolites-13-00965-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/4e64a63fdc39/metabolites-13-00965-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/5a0fa7af4bad/metabolites-13-00965-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/14346e71febd/metabolites-13-00965-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/44529352bd47/metabolites-13-00965-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9e/10456707/6be2a0faaecf/metabolites-13-00965-g009.jpg

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