Deuterated Arachidonic Acid Ameliorates Lipopolysaccharide-Induced Lung Damage in Mice

Abstract

Arachidonic acid (ARA) is a major component of lipid bilayers as well as the key substrate for the eicosanoid cascades. ARA is readily oxidized, and its non-enzymatic and enzymatic oxidation products induce inflammatory responses in nearly all tissues, including lung tissues. Deuteration at bis-allylic positions substantially decreases the overall rate of ARA oxidation when hydrogen abstraction is an initiating event. To compare the effects of dosing of arachidonic acid (H-ARA) and its bis-allylic hexadeuterated form (D-ARA) on lungs in conventionally healthy mice and in an acute lung injury model, mice were dosed with H-ARA or D-ARA for six weeks through dietary supplementation and then challenged with intranasal lipopolysaccharide (LPS) for subsequent analysis of bronchoalveolar lavage fluid and lung tissue. Dosing on D-ARA resulted in successful incorporation of D-ARA into various tissues. D-ARA significantly reduced LPS-induced adverse effects on alveolar septal thickness and the bronchoalveolar area. Oral deuterated ARA is taken up efficiently and protects against adverse LPS-induced pathology. This suggests novel therapeutic avenues for reducing lung damage during severe infections and other pathological conditions with inflammation in the pulmonary system and other inflammatory diseases.

Association between circulating fatty acid metabolites and asthma risk: a two-sample bidirectional Mendelian randomization study

“…Methylene groups and double bonds are different structural components of fatty acids; the number of methylene groups reflects the chain length of a fatty acid while the number of double bonds is related to the degree of unsaturation. As for the bis-allylic groups, it has been demonstrated in many studies that the bis-allylic hydrogen atoms are easily abstracted by peroxidase and participate in lipid peroxidation, and the oxidation products can induce inflammatory responses in almost all tissues, including pulmonary tissues [ 48 , 49 ]. Based on the results of previous research on PUFAs and FFA4, we speculated that traits related to the degree of unsaturation and chain length of fatty acid might play a protective role in asthma risk, whereas the bis-allylic group might promote the risk of asthma.…”

Deuterated Drugs and Biomarkers in the COVID-19 Pandemic

“…(a) Chemical Structures of ACH-3422 (22) and the Parent Drug PSI-7851 (23) ) substantially decreases the overall rate of oxidation when hydrogen abstraction is an initiating event. 51 The researchers also found that oral dosing with 35 resulted in successful incorporation of 35 into various tissues and significantly reduced E. coli lipopolysaccharide (LPS)-induced adverse effects in the lung area. This work therefore suggests novel therapeutic avenues for reducing lung damage during COVID-19 infection.…”

“…First, Habler et al developed and validated a two-dimensional isotope-dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) method for the accurate and simultaneous quantification of drugs in human serum, specifically for quantifying several repurposed COVID-19 drugs simultaneously. 70 The work was performed using stable deuterium-labeled analogues chloroquine-d 4 phosphate (47), hydroxychloroquine-d 4 sulfate (48), ritonavir-d 6 (49), lopinavir-d 8 (50), and azithromycin-13 C-d 3 (51) as internal MS standards (Figure 7), all commercially sourced. The dosage of repurposed COVID-19 therapeutics is typically derived from in vitro-generated half-maximum effective concentration (EC 50 ) values for SARS-CoV-2 and pharmacology-based pharmacokinetic models from other diseases and clinical conditions.…”

“…Thus, one strategy to interfere with the metabolism is by deuteration at the point of oxidation (Scheme a). Molchanova et al demonstrated that deuteration at the bisallylic positions within 34 to form 35 (Scheme b) substantially decreases the overall rate of oxidation when hydrogen abstraction is an initiating event . The researchers also found that oral dosing with 35 resulted in successful incorporation of 35 into various tissues and significantly reduced E.…”