β-Ionone is a close relative of β-carotenoids, which are found in a variety of fruits and vegetables[1]. β-ionone over 24 and 48 hours at 25, 50, 100, and 200 μM suppresses the proliferation of SGC-7901 cell line. 89 μM is the measured IC50 value[1].

Metabolism / Metabolites
A 3 kg male rabbit was orally administered 23 g of β-ionone (approximately 1000 mg/kg body weight/day) for 7 consecutive days. Urine was collected daily, and collection continued for 4 days after the last administration. Allyl epoxidation and ketone reduction yielded 3-oxo-ionone, 3-oxo-β-ionol, dihydro-3-oxo-β-ionol, and 3-hydroxy-β-ionol, which were detected in the urine. Unmodified β-ionone and glucuronide conjugates of 3-oxo-β-ionol and dihydro-3-oxo-β-ionol were also detected. In another experiment, three rabbits were fed 2-5 g of β-ionone daily in escalating doses, totaling approximately 30 g over a week. In another trial, rabbits were fed 4 g daily for two consecutive weeks, increasing to 5 g later. In this trial protocol, rabbits were not fed on certain days. Urine was collected from all animals and analyzed for the presence of metabolites. Identified metabolites included 3-oxo-β-ionone, pionol, dihydro-β-ionol, oxo-β-ionol, oxo-dihydro-β-ionol, and oxo-dihydro-β-ionone. Tetrahydro derivatives and various unsaturated products resulting from dehydrogenation were not detected. Two independent feeding trials, conducted in spring and autumn respectively, indicated that the hydrogenation of β-ionone to hydroxyl and carbonyl groups resulted in excretion in spring but not in autumn.

Toxicity Summary
Identification and Uses: β-Ionone (BI) is a colorless to pale straw-colored liquid. BI is used not only in fragrance manufacturing but is also a key intermediate in the synthesis of vitamins A, E, and K. Human Exposure and Toxicity: A 1% concentration of BI did not cause irritation or sensitization in patients. At a 5% concentration, two patients experienced suspected positive irritation, but no sensitization occurred. Animal Studies: No sensitization was observed in guinea pigs. In rabbits, mild to significant erythema appeared 24 hours after application of pure β-ionone to abraded and intact skin, and significant erythema appeared 72 hours later. Mild conjunctival irritation was observed in all three rabbits after application of pure BI at 0, 1, 2, and 4 hours. No adverse reactions were observed with BI in a 90-day rat feeding study. In a developmental study of BI-treated pregnant rats, compared with the untreated control group, the 1000 mg/kg dose group showed significantly increased uterine weight, embryo resorption/implantation rate, and litter resorption/implantation rate, while the litter live birth/implantation rate was significantly decreased; no such effects were observed in the 250, 500, and 750 mg/kg dose groups. At concentrations up to approximately 180 μg/plate, BI did not exhibit mutagenic activity against Salmonella typhimurium (strains TA98, TA100, TA1535, and TA1537), regardless of metabolic activation. Ecotoxicity studies: Transmission electron microscopy revealed that when Microcystis aeruginosa NIES-843 was exposed to BI at concentrations of 22.5 and 33.75 mg/L, thylakoids deformed, and the thylakoid membrane stacks began to disintegrate.

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Interaction
This study investigated the potential role of cytochrome P450 (P450) metabolic activation in thioacetamide-induced hepatotoxicity in male BALB/c mice. Mice were administered a P450 inducer, β-ionone (600 mg/kg), subcutaneously 72 and 48 hours before intraperitoneal injection of 100 or 200 mg/kg thioacetamide. Thioacetamide-induced increases in serum alanine aminotransferase and aspartate aminotransferase activities were significantly enhanced after β-ionone pretreatment. Furthermore, enhanced thioacetamide-induced hepatotoxicity was observed in liver histopathology. β-ionone pretreatment enhanced thioacetamide-induced liver necrosis. In liver microsomes, β-ionone treatment significantly induced the activities of P450 2B-specific pentoxyhalogen O-depentylase and benzyloxyhalogen O-debenzylate.
β-ionone can also induce the activity of other P450-related monooxygenases. Since β-ionone pretreatment itself is not hepatotoxic at P450-inducing doses, our current results suggest that β-ionone may be a useful P450 enzyme inducer model for studying the toxic mechanisms of certain chemicals requiring P450 metabolic activation in mice. Female ICR mice were treated, alone or in combination, with cocaine and several cytochrome P450 (CYP) inducers, such as phenobarbital, β-ionone, dexamethasone, and β-naphthylflavonoid. Cocaine-induced hepatotoxicity was first observed after pretreatment with phenobarbital, β-ionone, or dexamethasone, consistent with a significant increase in cocaine N-demethylation (the first step in cocaine bioactivation). Phenobarbital and β-ionone-induced liver injury was located in the periportal region (zone 1), while dexamethasone-induced liver injury was located in the perivenule region (zone 3). To elucidate the effects of CYP inducer pretreatment, we determined the activities of CYP isoenzyme-specific enzymes. β-Naphthoflavone induced CYP1A and 2B but had no effect on cocaine-induced hepatotoxicity. On the other hand, β-ionone enhanced hepatotoxicity but did not induce CYP3A. The activity of cocaine N-demethylases was significantly positively correlated with the activities of CYP2A (r=0.83) and CYP2B (r=0.81). The addition of the CYP2A-specific inhibitor 8-methoxypsoralen significantly inhibited cocaine N-demethylation. Furthermore, in phenobarbital-treated mice, 8-methoxypsoralen pretreatment significantly inhibited cocaine-induced hepatotoxicity. These results indicate that cocaine-induced hepatotoxicity in female mice is partly mediated by CYP2A, which is involved in the N-demethylation of cocaine. β-ionone exhibited potent anticancer activity both in vitro and in vivo. We determined tumor incidence, number of tumor-bearing rats, and cell proliferation and apoptosis in a 7,12-dimethylbenzo[a]anthracene (DMBA)-induced rat breast cancer model. Rats were fed an AIN-76A diet containing β-ionone (0, 9, 18, or 36 mmol/kg) for 24 weeks starting 2 weeks before DMBA administration. A dose-dependent inhibitory effect of dietary β-ionone on breast cancer development was observed. The corresponding tumor incidence rates were 82.1%, 53.3%, 25.9%, and 10.0%, respectively (p < 0.01 or 0.05). With increasing dietary β-ionone intake, the time to tumor appearance was prolonged, and the number of tumors decreased. Histopathological and immunohistochemical evaluations were performed on 64, 31, 15, and 3 tumors from each group (n=30 per group), respectively. In the latter group, the proportions of adenocarcinoma, adenoma, and benign masses were evenly distributed. In other groups, the proportions of adenocarcinoma and benign masses decreased with increasing dietary β-ionone intake, while the proportion of benign masses increased. Expression of proliferating cell nuclear antigen (PCNA), cyclin D1, and Bcl-2 was decreased, while Bax expression and nuclear fragmentation increased with increasing dietary β-ionone intake. These results indicate that dietary β-ionone has a significant inhibitory effect on DMBA-induced mammary cancer in rats. β-ionone (BI) is a degraded (C13) sesquiterpene found in plant essential oils. It has been used in the synthesis of fragrance chemicals and vitamin A. Recently, BI has been reported as a potent in vitro inhibitor of CYP2B1-catalyzed reactions in rat liver microsomes. This study aimed to investigate whether the inhibitory effect of BI on the CYP2B1 response could alleviate cyclophosphamide (CP)-induced embryotoxicity in rats. In preliminary experiments, a dose-dependent prolongation of pentobarbital sleep time in male and female Wistar rats indicated that BI also inhibits CYP2B1 in vivo. In the second experiment, on day 11 of gestation, rats were administered BI (0, 250, 500, 750, or 1000 mg/kg body weight) by gavage 45 minutes before subcutaneous injection of CP (7.5 mg/kg body weight) or its solvent (saline). BI alone, even at the highest tested dose, resulted in a high proportion of embryo resorption. However, lower doses of BI significantly attenuated CP-induced embryolethality and teratogenicity. These results appear to support the view that, in rats, CYP2B1 plays a crucial role in the conversion of CP into its embryolet-lethal and teratogenic metabolites.

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Non-human toxicity values
Oral LD50 in rats: 4590 mg/kg
Intraperitoneal LD50 in mice: 2277 mg/kg

[1]. β-Ionone and Its Analogs as Promising Anticancer Agents. Eur J Med Chem. 2016 Nov 10;123:141-154.

β-Ionone is a colorless to pale yellow liquid with a cedarwood scent. In very dilute alcohol solutions, its aroma is similar to that of violets. It is used in perfume making. β-Ionone is a but-3-en-2-one derivative with a 2,6,6-trimethylcyclohexyl-1-en-1-yl substitution at the 4-position. It possesses both antioxidant and fragrance properties. β-Ionone has been reported to be found in tea (Camellia sinensis), perilla (Perilla frutescens), and other organisms with relevant data. β-Ionone is a metabolite of or produced by the yeast Saccharomyces cerevisiae.

C13H20O

192.30

192.151

14901-07-6

638014

Colorless to light yellow liquid

0.9±0.1 g/cm3

254.8±0.0 °C at 760 mmHg

-49ºC

121.3±11.9 °C

0.0±0.5 mmHg at 25°C

1.518

3.85

0

1

2

14

292

0

CC1=C(C=CC(=O)C)C(C)(C)CCC1

PSQYTAPXSHCGMF-BQYQJAHWSA-N

InChI=1S/C13H20O/c1-10-6-5-9-13(3,4)12(10)8-7-11(2)14/h7-8H,5-6,9H2,1-4H3/b8-7+

(E)-4-(2,6,6-trimethylcyclohexen-1-yl)but-3-en-2-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100 mg/mL (520.02 mM)
Ethanol: 100 mg/mL (520.02 mM)
H2O: < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (13.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (13.00 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (13.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)