beta-ionone and Abnormalities--Drug-Induced

β-ionone (BIO) is used in fragrances, toiletries and non-cosmetic products, and as a flavor food additive. Notwithstanding the widespread human exposure, there are limited data on the reproductive toxicity of BIO. This study evaluated the developmental toxicity of BIO (0, 125, 250, 500 and 1000 mg/kg body weight/day) given orally to rats on days 6-15 of gestation (GD6-15). C-section was on GD21 and implantations, living and dead fetuses and resorptions were recorded. Fetuses were weighed, and examined for external abnormalities and skeleton and visceral anomalies. The embryotoxicity of a single oral dose of BIO (1000 mg/kg body wt) given on GD11 was evaluated as well. At the highest dose, BIO reduced weight gain and produced chromodacryorrhea and other signs of toxicity. BIO did not increase the frequency of malformations nor did it retard fetal growth. Nonetheless, BIO decreased the pregnancy rate in the group of females exposed on GD6-15, and increased the resorption rate in those treated on GD11 only. In conclusion, except for a higher embryolethality at a maternally toxic dose, BIO caused no embryotoxic effect over the dose range tested and the study NOAEL for maternal and developmental toxicity was 500 mg of BIO/ kg of body weight/day.

Topics: Abnormalities, Drug-Induced; Animals; Dose-Response Relationship, Drug; Female; Male; Norisoprenoids; Rats; Rats, Wistar; Weight Gain

Beta-ionone (BI) is a degraded (C 13) sesquiterpene found in plant essential oils. It has been used in the synthesis of perfume chemicals and vitamin A. Recently, it was reported that BI is a rather potent in vitro inhibitor of CYP2B1-catalysed reactions in rat liver microsomes. The present study was performed to investigate whether inhibition of CYP2B1 reactions by BI could lead to an attenuation of cyclophosphamide (CP)-induced embryotoxicity in the rat. In a preliminary experiment, a dose-dependent prolongation of pentobarbital sleeping time in male and female Wistar rats suggested that BI inhibits CYP2B1 in vivo as well. In a second experiment, rats were treated by gavage with BI (0, 250, 500, 750 or 1000 mg/kg body wt) 45 min prior to a subcutaneous injection of either CP (7.5 mg/kg body wt) or its vehicle (saline) on day 11 of pregnancy. BI alone, at the highest dose tested, caused a high proportion of resorptions. Lower doses of BI, however, clearly attenuated CP-induced embryolethality and teratogenicity. These results seem to support the view that, as far as rats are concerned, CYP2B1 plays an important role in the conversion of CP into its embryolethal and teratogenic metabolites.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Cyclophosphamide; Cytochrome P-450 CYP2B1; Drug Interactions; Enzyme Inhibitors; Female; Fetal Death; Fetal Resorption; Hypnotics and Sedatives; Male; Norisoprenoids; Pentobarbital; Pregnancy; Rats; Rats, Wistar; Sleep; Terpenes