Inhibition of cyclophosphamide-induced teratogenesis by beta-ionone.
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.
Gomes-Carneiro
M R
MR
Laboratory of Environmental Toxicology, National School of Public Health, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
De-Oliveira
A C A X
AC
De-Carvalho
R R
RR
Araujo
I B
IB
Souza
C A M
CA
Kuriyama
S N
SN
Paumgartten
F J R
FJ
D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D001835:Body Weight; D003520:Cyclophosphamide / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000633:toxicity*; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D005327:Fetal Resorption / Q000139:chemically induced; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D045792:Norisoprenoids; D010424:Pentobarbital / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012890:Sleep / Q000187:drug effects; D013729:Terpenes / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D045792:Norisoprenoids; D013729:Terpenes; D003520:Cyclophosphamide; C008157:beta-ionone; D019362:Cytochrome P-450 CYP2B1; D010424:Pentobarbital