Senecionine N-oxide

• CAS: 13268-67-2
• Catalog Number: ACM13268672
• Category: Main Products
• Molecular Weight: 351.397
• Molecular Formula: C₁₈H₂₅NO₆
• Synonyms: senecionine N-oxide;12-Hydroxysenecionan-11,16-dione 4-oxide;Senecionine oxide;Senecionin-N-oxid
• IUPAC Name: Senecionine, N-oxide
• Exact Mass: 351.16800
• Packing Group: II

Case Study

Toxicokinetic Study of Senecionine N-Oxide

Yang M, et al. Archives of toxicology, 2017, 91, 3913-3925.

The study reported evidence that pyrrolizidine alkaloid (PA) N-oxides can induce hepatic sinusoidal obstruction syndrome (HSOS) in humans. Among them, seneciopine N-oxide, as a representative PA N-oxide, was used to study its toxicokinetics by a single oral administration of seneciopine N-oxide (55 μmol/kg) to rats.
Toxicokinetics of seneciopine N-oxide
· In the group treated with senecionine N-oxide, senecionine was clearly identified as the sole detectable metabolite in the plasma. The kinetic profiles for both the administered senecionine N-oxide and its metabolite, senecionine, were similar; however, systemic exposure to senecionine was significantly lower compared to that of senecionine N-oxide, and senecionine achieved its maximum concentration much faster than senecionine N-oxide.
· Additionally, after oral administration, senecionine N-oxide gradually reached its peak plasma concentration, indicating a slower absorption rate. Following administration, senecionine N-oxide was quickly converted to senecionine, as evidenced by the notably shorter time to reach maximum concentration (Tmax) for senecionine, which then sustained elevated levels for over 11 hours.
· Pyrrole-protein adducts were transformed into senecionine, which underwent metabolic activation to produce a reactive metabolite capable of interacting with proteins to form pyrrole-protein adducts.

Physiologically based kinetic modeling of senecionine N-oxide.

Widjaja, Frances, et al. Frontiers in Pharmacology 14 (2023): 1125146.

More than 1,000 pyrrolizidine alkaloids (PAs) and their N-oxides (PA-N-oxides) are present in 3% of all flowering plants. PA-N-oxides are toxic when reduced to their parent PAs, which are bioactivated to pyrrole intermediates that produce protein and DNA adducts, leading to hepatotoxicity and carcinogenicity. Literature data for Senecionine N-oxide indicate that the relative potency (REP) value of this PA-N-oxide compared to its parent PA senecionine varies with the endpoint used. This study aimed to investigate the mode of action of the endpoint-dependent REP values of Senecionine N-oxide using a physiologically based kinetic (PBK) model. The results of this study demonstrate how the REP values of Senecionine N-oxide depend on the dose and endpoint used, and that PBK modeling provides a method to characterize the REP values of PA-N-oxides at realistic low dietary exposure levels, thereby reducing the need for animal experiments.
The PBK model of senecioin N-oxide has a previously developed and evaluated rat SEN submodel running as an ODE solver. The model was extended to include GSH clearance of the reactive pyrrole intermediate through SEN to form 7-GS-DHP, where 7-GS-DHP is the major metabolite formed in this reaction. All other physiological, physicochemical, and kinetic parameters remained unchanged from the previous code. PBK simulated REP values when calculating with a modified fraction from 0.125 to 0.400 bioactivated. In this calculation, the amount of 7-GS-DHP was assumed to remain constant, which was obtained with a fraction bioactivated of 0.200 and kof 0.0023 and 0.00145 ml minmgS9 for the formation of 7-GS-DHP when administering senecioin N-oxide and SEN, respectively. As the bioactivated fraction increased, more pyrrole-protein adducts were formed when the amount of 7GS-DHP remained constant.

Role of senecionine N-oxide in insect chemical defenses

Lindigkeit, Rainer, et al. European Journal of Biochemistry 245.3 (1997): 626-636.

Larvae of Creatonotos transiens (Lepidoptera, Arctiidae) and Zonocerus variegatus (Orthoptera, Pyrgomorphidae) ingested 14C-labeled senecionine and senecionine N-oxide with equal efficiency but sequestered both tracers only in the N-oxide form. Larvae of the non-sequestering Spodoptera littoralis efficiently eliminated the ingested alkaloids. During feeding on both alkaloid forms, transient levels of senecionine (but not N-oxide) accumulated in the hemolymph of S. littoralis larvae. Based on these results, senecionine [*80]N-o~ide was fed to C. transiens larvae and Z. variegatus adults. Senecioide Noxide recovered from the hemolymph of both insects showed an almost complete loss of the "0 label, indicating a reduction in the orally fed N-oxide in the gut, the uptake of tertiary alkaloids and their reN-oxidation in the hemolymph.
Insects were fed with 1 mg of Senecioide or Senecioide N-oxide, respectively, containing 5 lo5 cpm of the corresponding tracer. The tracer was incorporated into small pieces of the corresponding artificial diet (Spodoptera exigua, Creatunotos) or applied on glass fiber discs (10 mm diameter) (Zonocerus) and presented to insects previously starved for 12 h. After consumption of the labeled diet, insects were allowed to continue feeding on an untreated diet or Chinese cabbage (Zonocerus) for 48 h. Excreta were collected at intervals if needed (Spudoptera). At the end of the experiment, individuals were pulverized in liquid nitrogen and washed with 10 ml methanol/25% HCl (100:1, volume). After centrifugation, the precipitate was extracted twice in the same manner. Aliquots were taken for estimation of total radioactivity by scintillation counting and for TLC separation of labeled senecioine and its N-oxide.