Dihydro-Cucurbitacin-E; a Secondary Metabolite of Curvularia lunata's Biotransformation as a Promising cPLA-2 and sPLA-2 Inhibitor in B[a]P-Induced Lung Toxicity

Lung cancer is the most common cause of mortality, and its prevalence is rising quickly, making it a major global health concern. Numerous studies have indicated that benzo(a)pyrene [B[a]P] in cigarette smoke is the main cause of lung toxicity.

The study's goal was to apply Curvularia lunata NRRL 2178 in biotransformation cucurbitacin-E-glucoside to dihydro-cucurbitacin-E (DHCE). We characterized the isolated DHCE using 1H-NMR and ¹³C-NMR spectra. We extended our study to evaluate the cancer activity of DHCE against A-549 cells in vitro, as well as its lung protective activity against B[a]P-induced lung toxicity.

We incubated Curvularia lunata NRRL 2178 with cucurbitacin-E-glucoside DHCE for 14 days. We isolated and characterized the obtained metabolite, DHCE, using 1H-NMR and ¹³C-NMR techniques. We also evaluated the IC₅₀ of the isolated DHCE against A-549 cells. On the other hand, we conducted in vivo studies to assess its lung protective effect against B[a]P-induced toxicity in mice.

The results of the ¹H-NMR and ¹³C-NMR experiments showed that the metabolite, DHCE, was found because it lacked two trans-olefinic protons (23 and 24) and the hydrogen atoms of the glucose moiety in the cucurbitacin-E-glucoside skeleton structure. The IC50 value of DHCE against A-549 cells is 38.87 µg/mL, respectively. The LD50 of DHCE was 930 mg/kg b.w. Giving DHCE (18.6 and 46.5 mg/kg b.w.) orally to mice that had been given B[a]P (20 mg/kg b.w.) every day for 30 days made their plasma total cholesterol (TC), triglycerides (TG), and high density lipoprotein-c (HDL-C) levels much better, as well as their lung reduced glutathione (GSH), catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels, compared to mice that had been given B[a]P. On the other hand, oral administration of DHCE enhanced plasma interleukin-6 (IL-6) and nuclear factor (NF)-κB, as well as matrix metalloproteinases-2 (MMP-2) and MMP-12, in the lung of treated mice. On the other hand, administering DHCE to lung mice treated with B[a]P reduced the activity of crucial genes linked to lung inflammation, specifically cytosolic (cPLA2) and Secretory Phospholipase A2 (sPLA2). Furthermore, DHCE nearly normalized these effects in lung histoarchitecture.

The obtained biochemical, molecular biology, and histological results proved the lung protective activity of Curvularia lunata metabolite (DHCE) against B[a]P-induced lung toxicity in mice.