title: Liarozole, an inhibitor of retinoic acid metabolism, exerts retinoid-mimetic effects in vivo.
abstract: Liarozole is an imidazole-containing compound that inhibits the cytochrome P-450-dependent metabolism of all-trans-retinoic acid (RA). In vitro, liarozole (IC50, 2.2 microM) suppressed the P-450-mediated conversion of RA to more polar metabolites by hamster liver microsomes. In vivo, it enhanced the plasma level of RA from mostly undetectable values (less than 0.5 ng/ml) in control rats to 1.4 +/- 0.1 and 2.9 +/- 0.1 ng/ml in animals treated p.o. with 5 and 20 mg/kg of liarozole, respectively. Moreover, liarozole possessed antikeratinizing activity: when dosed subchronically (5-20 mg/kg, once daily for 3 days) to ovariectomized rats, the compound reversed the vaginal keratinization induced in these animals by estrogenic stimulation. Dose response experiments indicated that the antikeratinizating effect of liarozole was as potent as that of RA. One-dimensional electrophoresis and immunoblotting of extracted vaginal epithelia showed that liarozole shared with RA the ability to inhibit the synthesis of high molecular weight (57-60 kDa) keratin proteins, and to enhance the expression of the 45 to 47 kDa keratin polypeptides. Furthermore, we found that antikeratinizing doses of liarozole doubled the RA concentration in the vagina of ovariectomized rats: the mean amount of RA extracted from 200 mg of vaginal tissue was increased from 1.1 +/- 0.1 ng in vehicle-treated animals to 2.2 +/- 0.2 and 2.6 +/- 0.2 ng after treatment with 5 and 20 mg/kg of liarozole, respectively. These findings indicate that liarozole, an inhibitor of RA metabolism and RA produce similar morphologic and biochemical effects on the differentiation process of rat vaginal epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Janssen Research Foundation, Beerse, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Van Wauwe
authors.forename: G
authors.initials: G
authors.lastname: Van Nyen
authors.forename: M C
authors.initials: MC
authors.lastname: Coene
authors.forename: P
authors.initials: P
authors.lastname: Stoppie
authors.forename: W
authors.initials: W
authors.lastname: Cools
authors.forename: J
authors.initials: J
authors.lastname: Goossens
authors.forename: P
authors.initials: P
authors.lastname: Borghgraef
authors.forename: P A
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007633:Keratins / Q000302:isolation & purification; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010052:Ovariectomy; D051381:Rats; D011919:Rats, Inbred Strains; D014212:Tretinoin / Q000097:blood / Q000378:metabolism*; D014621:Vagina / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D014212:Tretinoin; D007633:Keratins; C061121:liarozole