Role of liquid membrane phenomenon in the biological actions of thioridazine.

Role of surface activity in the mechanism of action of thioridazine (THR) has been studied. THR has been shown to generate liquid membrane it self and also in association with the relevant membrane lipids, sphingomyelin and cholesterol in series with a supporting membrane. Transport of relevant biogenic amines e.g. dopamine, nor-adrenaline, adrenaline, serotonin, gamma amino butyric acid (GABA) and glutamic acid and ions viz. sodium, potassium, and calcium has been studied in the presence of liquid membranes generated by THR and THE in association with sphingomyelin-cholesterol. The data on modifications in the permeability of relevant biogenic amines and ions indicate that the liquid membranes generated by THR may contribute to the mechanism of action of THR.

Role of surface activity in the biological actions of ranitidine and famotidine.

The role of surface activity has been studied in the biological actions of ranitidine (RNT) and famotidine (FMT). The drugs have been shown to generate liquid membranes in series with a supporting membrane with the virtue of their amphiphilicity. Transport of histamine, acetylcholine, and ions (chloride, bicarbonate, potassium, sodium and calcium) have been studied in the presence of liquid membranes generated by surface-active RNT and FMT. The data on the modifications in the permeability of histamine, acetylcholine and ions indicate that the liquid membranes generated by RNT and FMT may play a significant role in their biological action. The surface-active nature of the drugs has been discussed with relevance to their pharmacological effects.

Transport across liquid membranes containing vitamin A (retinol acetate).

The role of the surface activity of vitamin A has been studied in the light of the liquid membrane hypothesis of drug action. Transport of relevant amino acids such as serine, threonine, arginine, and histidine and various ions such as calcium, sodium, and potassium in the presence of liquid membranes generated by vitamin A has been studied. The data on the modifications in the permeability of relevant amino acids and ions indicate that the liquid membranes generated by vitamin A may also play a significant role in its physiological action.

Transport studies through liquid membranes of ciprofloxacin and norfloxacin.

Ciprofloxacin and norfloxacin, the widely used drugs have been shown to generate liquid membranes in series with a supporting membrane (Sartorius celluose acetate microfiltration membrane). Transport of dextrose and ions, such as NH4+, Mg2+, Ca2+, K+ and PO4(3-) has been studied in the presence of liquid membranes generated by these drugs. The data obtained on the modification in the permeability of dextrose and ions in the presence of liquid membrane indicate the significance of liquid membranes in passive transport.

Tumorigenicity of racemic and optically pure bay region diol epoxides and other derivatives of the nitrogen heterocycle dibenz[a,h]acridine on mouse skin.

CD-1 female mice were initiated with a single topical application of 500 nmol dibenz[a,h]acridine (DB[a,h]Acr), its racemic trans-1,2-, 3,4-, 8,9- and 10,11-dihydrodiols, racemic DB[a,h]Acr 3,4-diol 1,2-epoxide-1 and -2 or racemic DB[a,h]Acr 10,11-diol 8,9-epoxide-1 and -2, where the benzylic hydroxyl group is either cis (isomer 1) or trans (isomer 2) to the epoxide oxygen. The mice were subsequently treated twice weekly with 12-O-tetradecanoylphorbol 13-acetate for 25 weeks. High tumorigenicity was observed only for DB[a,h]Acr, its 10,11-dihydrodiol and DB[a,h]Acr 10,11-diol 8,9-epoxide-2 (3.3, 1.2 and 1.6 tumors/mouse, respectively). The tumor-initiating activity of a 50 nmol dose of DB[a,h]Acr and the optically active (+)- and (-)-enantiomers of DB[a,h]Acr 10,11-dihydrodiol and of the optically active DB[a,h]Acr 10,11-diol 8,9-epoxide-1 and -2 were also studied. Only DB[a,h]Acr, (-)-DB[a,h]Acr (10R,11R)-dihydrodiol and the bay region (+)-(8R,9S,10S,11R)-diol epoxide-2 were highly active (1.6, 1.7 and 2.4 tumors/mouse, respectively). These results are consistent with previous studies which showed that the corresponding bay region RSSR diol epoxides of benzo[a]pyrene, benz[a]anthracene, chrysene and benzo[c]phenanthrene as well as the aza-polycyclic dibenz[c,h]acridine are the most tumorigenic isomers.

Stereoselective metabolism of dibenz[a,h]acridine to bay-region diol epoxides by rat liver microsomes.

The carcinogen dibenz[a,h]acridine (DB[a,h]ACR is metabolized predominantly to trans-3,4-dihydroxy-3,4-dihydro-dibenz[a,h]acridine (DB[a,h]ACR-3,4-diol) and the proximate carcinogen trans-10,11-dihydroxy-10,11-dihydrodibenz[a,h]acridine (DB[a,h]ACR-10,11-diol) [Steward et al. (1987) Carcinogenesis, 8, 1043-1050]. In the present investigation, the stereoselectivity of rat liver enzymes in metabolism of DB[a,h]ACR to its 3,4-diol and 10,11-diol and of DB[a,h]ACR-10,11-diol enantiomers to their bay-region diol epoxides has been examined with liver microsomes from control and 3-methylcholanthrene-treated rats. Both microsomal preparations produced the major metabolites DB[a,h]ACR-3,4-diol and DB[a,h]ACR-10,11-diol containing predominantly R,R-enantiomers with 38-54% optical purity. Metabolism of (-)-(10R,11R)- and (+)-(10S,11S)-enantiomers of DB[a,h]ACR-10,11-diol by liver microsomes from control rats produced predominantly bay-region diol epoxides (46-59% of total metabolites), whereas very little bay-region diol epoxides (14-17% of total metabolites) were produced by liver microsomes from 3-methylcholanthrene-treated rats. The bay-region diol epoxides produced in these studies consisted of predominantly DB[a,h]ACR-10,11-trans-diol epoxide diastereomer in which the benzylic hydroxyl group and epoxide oxygen are trans. However, (-)-DB[a,h]ACR-10R,11R-diol, a major metabolite of DB[a,h]ACR, was metabolized by liver microsomes from 3-methylcholanthrene-treated rats to (+)-[8R,9S,10S,11R]-DB[a,h]ACR-10,11-trans-diol epoxide, a diastereomer which displayed high mutagenic activity in V79 cells, in an amount which was 6.5-fold greater than that of the corresponding cis-diol epoxide diastereomer. The relative amounts of trans-diol epoxide versus cis-diol epoxide in the mixture of bay-region diol epoxides produced from DB[a,h]ACR-10R,11R-diol and DB[a,h]ACR-10S,11R-diol with liver microsomes from control rats and from DB[a,h]ACR-10S,11S-diol with liver microsomes from 3-methylcholanthrene-treated rats were 1.7, 2.1 and 2.3 respectively.

Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,l]pyrene syn- and anti-fjord-region diolepoxides.

Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among polycyclic aromatic hydrocarbons. Because the fjord-region diolepoxide (DE) pathway is one of the mechanisms of activation, (+/)-trans-DB[a,l]P-11,12-dihydrodiol, (+/-)-anti-DB[a,l]PDE and (+/-)-syn-DB[a,l]PDE were synthesized. The key intermediate for these syntheses, 12-methoxy-DB[a,l]P, was successfully obtained by cyclization of 6-(3-methoxybenzyl)benzanthrone with methanesulfonic acid, which in turn was prepared by 1,4 conjugate addition of 3-methoxybenzyl magnesium bromide to benzanthrone. The presence of the DB[a,l]P nucleus in the dihydrodiolepoxides and diolepoxides was proven by conversion of 12-methoxyDB[a,l]P into the parent compound in several steps. The tumor-initiating activity of the two diolepoxides in mouse skin was compared to that of DB[a,l]P-11,12-dihydrodiol and the parent DB[a,l]P. Groups of 24 8 week old female SENCAR mice were topically initiated with 12, 4 or 1.33 nmol of compound in 100 microliters of acetone. Starting 1 week later, promotion with 12-O-tetradecanoylphorbol-13-acetate (1.62 nmol in 100 microliters acetone) was begun and continued twice weekly for 30 weeks. At the 12, 4 and 1.33 nmol doses, anti-DB[a,l]PDE induced 2.0, 0.7 and 0.7 tumors per mouse (t/m) respectively, whereas syn-DB[a,l]PDE induced 1.8, 1.5 and 1.8 t/m. At the same three doses, DB[a,l]P-11,12-dihydrodiol induced 4.6, 4.3 and 2.8 t/m, and DB[a,l]P resulted in 9.3, 7.1 and 5.2 t/m. These results confirm that DB[a,l]P is more potent than its 11,12-dihydrodiol and show that the two diolepoxides are less tumorigenic than their precursors. At the medium and low doses, syn-DB[a,l]PDE is more tumorigenic than its congener anti-DB[a,l]PDE.

Bacterial and mammalian cell mutagenicity of four optically active bay-region 10,11-diol-8,9-epoxides of the nitrogen heterocycle dibenz[a,h]acridine.

The mutagenic activities of the enantiomers of the diastereomeric pair of bay-region 10,11-diol-8,9-epoxides of dibenz[a,h]acridine (DB[a,h]ACR) were evaluated in histidine-dependent strains of Salmonella typhimurium and in cultured Chinese hamster V79 cells. In strains TA98 and TA100 of S.typhimurium, the (-)-[8S,9R,10R,11S] diol-epoxide was the most mutagenic compound, inducing 1200 and 6900 His+ revertants/nmol respectively. The mutagenic activity of each of the remaining three isomers was essentially independent of the bacterial strain used and had 14-72% of the activity of the [S,R,R,S] isomer. However, in Chinese hamster V79 cells, the (+)-[8R,9S,10S,11R] diol-epoxide was the most mutagenic compound (68 8-azaguanine resistant variants/nmol/10(5) cells), inducing from 2 to 11 times as many mutations as the other three isomers. These results are analogous to previous studies with the bay-region diol-epoxides of other polycyclic hydrocarbons in that the isomer with [R,S,S,R] absolute configuration has had variable activity in the bacterial assays, but has generally been the most active in the mammalian cells. Furthermore, this isomer has almost always been highly tumorigenic in the mouse.

Mutagenicity of dibenz[a,c]anthracene and its derivatives in Salmonella typhimurium TA100.

The mutagenic activities of dibenz[a,c]anthracene (DB[a,c]A), and its 11 derivatives, including 3 diols, 6 phenols and 2 oxepines, were studied in the TA100 strain of Salmonella typhimurium at doses varying from 0 to 20 micrograms/plate in the presence of a rat-liver S9 (9000 x g) preparation. Among the diols of DB[a,c]A tested DB[a,c]A-10,11-diol was the most mutagenic compound. However, it was consistently less mutagenic than the parent hydrocarbon. Oxepine-1 and oxepine-2 which are believed to be the photoisomerized products of DB[a,c]A-1,2 oxide and DB[a,c]A-3,4-oxide, respectively, were also less mutagenic than DB[a,c]A. In contrast to these results, 4-hydroxyDB[a,c]A was almost twice as active as DB[a,c]A, and 2-hydroxy- and 3-hydroxyDB[a,c]A were even more (4-6-fold) mutagenic than DB[a,c]A. The remaining phenols were relatively inactive or weakly active in this mutagenicity assay. These results provide initial evidence that the bay-region theory may not be applicable to the mutagenesis of DB[a,c]A, and that the angular ring substituted phenols of DB[a,c]A may be involved in the metabolic activation of this highly mutagenic hydrocarbon.

Studies on Centchroman, a new antifertility compound.

PIP: This paper reports the results of laboratory research on the chemical properties, analytic specifications, assay method, and stability of centchroman--3,4-trans-2,2-Dimethyl-3-phenyl-4(p-beta-pyrrolidinoethoxy)-7-methoxychromanhydrochloride. This compound has been reported to possess potent antifertility activity, anti-inflammatory activity, and to induce ovulation in anovulatory women. The crystalline compound is almost insoluble in water and has a pKa value of 2.1. Ultraviolet spectrophometric and colorimetric tests produced 98-102% recovery of added centchroman. Further studies indicated that the compound remains stable under storage conditions for 3 1/2 years, with no marked change in color and general appearance. Finally, no change in general appearance, purity, ultraviolet pattern, and assay were observed after the compound was heated at 105 degrees for 6 hours. Although the above tests involved the pure compound, additional tests with the tablet form revealed 100% stability even after 3 years of storage, again with no change in color or general appearance.^ieng