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Pigmented epithelial cells isolated from 8-9-day-old chick embryos can transdifferentiate into lens-like cells at the terminal period of the third generation of culture. However, efficiency of this transdifferentiation is usually rather low. Phenylthiourea, a potent inhibitor of melanin synthesis, effectively enhances transdifferentiation of pigmented epithelial cells into lens-like cells in vitro. Lentoid bodies began to appear in the multilayered region of primary cultures of pigmented epithelial cells maintained in medium containing phenylthiourea at concentrations between 0.5 and 1.0 mM. Furthermore, the enhancing effect of phenylthiourea can be amplified with testicular hyaluronidase. Under these conditions, pigmented epithelial cells grow vigorously and lose their differentiative properties, efficiently switching their phenotype into lens-like cells some 20 days after initiation of culture in the presence of both substances. Semiquantitative analysis revealed that testicular hyaluronidase amplified the effect of phenylthiourea more than 100-fold. It has been suggested that phenotypic expression of pigmented epithelial cells during transdifferentiation can be regulated by manipulating the microenvironment in which these cells reside.
For the purpose of developing a transglutaminase inhibitor which could be effective in physiological and pharmacological studies, a series of phenylthiourea derivatives of alpha, omega-diaminoalkanes were designed, synthesized, and evaluated kinetically as inhibitors of transglutaminases. A homologous series of compounds of the structure phenylthiourea-(CH2)n-NH2, where n = 2, 3, 4, 5, and 6, were tested for the inhibition of both guinea pig liver transglutaminase-catalyzed amine incorporation into various glutamine-containing substrates and plasma transglutaminase (factor XIIIa)-catalyzed amine incorporation into fibrin and fibrin cross-linking. It was found that the inhibitory activity of the compounds increases with increasing number of methylene groups in the side chain up to a maximum of n = 5. A further increase in the length of the methylene side chain to n = 6 results in decreased activity. The Ki value (4.9 X 10(-5) M) of 1-(5-aminopentyl)-3-phenylthiourea (PPTU) (n = 5) for the inhibition of guinea pig transglutaminase-catalyzed amine incorporation into the B chain of oxidized insulin is in close agreement to its Km(app) value (7.1 X 10(-5) M) obtained using 14C-labeled PPTU. PPTU was also found to be a potent inhibitor of plasma transglutaminase-catalyzed fibrin cross-linking. The finding that the specificity of the alkylamines for inhibition is correlated with the length of their methyl side chains is compatible with those reported for aliphatic amines and monodansylcadaverine analogues (where dansyl is 5-dimethylaminonaphthalene-1-sulfonyl). The phenylthiourea derivatives, however, are far less toxic in mice than monodansylcadaverine as indicated by their LD50 values: PPTU, 400 +/- 25 mg/kg; and monodansylcadaverine, 160 +/- 20 mg/kg.
The synthesis in excellent yields of 1-acyl-3-furfuryl-1-phenylthioureas 2 by reacting at t less than or equal to 10 degrees C 3-furfuryl-1-phenylthiourea 1, prepared in situ from furfurylamine and phenyl isothiocyanate, with aromatic or heterocyclic acyl chlorides in pyridine solution is described. 1-Acylthioureas 2 rearranged in high yields to 3-acylthioureas 3 by treatment with sodium hydroxide in heterogeneous phase. 1,3-Diacyl-3-furfuryl-1-phenylthioureas 4 were obtained in satisfactory yields by treatment of 1 with two moles of acyl chloride as in the case of 1-monoacylation. The thiourea 1 prepared in situ reacted with iodomethane in dimethylformamide solution and in the presence of sodium hydride to give in high yield the S-methyl derivative, namely the methyl ester of N-phenyl-1-furfurylaminethiocarboximidic acid. Some acylthioureas 2 and 4 showed a platelet antiaggregating activity in vitro superior or comparable to that of acetylsalicylic acid. The 1,3-diacylthiourea 4 c exhibited an appreciable anticonvulsant activity in mice and some compounds 2 and 4 moderate competitive antiacetylcholine and H1-antihistamine effects in vitro.
New 1-benzhydryl-3-phenylurea derivatives and their 1-benzhydryl-3-phenylthiourea isosteres were synthesized and evaluated for their human CB1 and CB2 cannabinoid receptor affinity. These compounds proved to be selective CB1 cannabinoid receptor ligands, acting as inverse agonists in a [35S]-GTPgammaS assay. The affinity of 3,5,5'-triphenylimidazolidine-2,4-dione and 3,5,5'-triphenyl-2-thioxoimidazolidin-4-one derivatives, possessing the 1-benzhydryl-3-phenylurea and 1-benzhydryl-3-phenylthiourea moiety, respectively, was also evaluated. In conclusion, the 1-benzhydryl-3-phenylurea scaffold seems to be a new interesting template of CB1 cannabinoid receptor inverse agonists.
In a series of Caucasian patients over the age of 40 years, the number of individuals unable to recognize the bitter taste of phenylthiourea (8.1 mg/100 ml) was found to be 28 percent in a "normal" eye clinic population (446 individuals), 17 percent in a series of 155 patients with angleclosure glaucoma, and 53 percent in 211 patients with primary open-angle glaucoma.
Melanocytes and neuroblasts share the property of transforming L-tyrosine through two distinct metabolic pathways leading to melanogenesis and catecholamine synthesis, respectively. While tyrosinase (TYR) activity has been shown to be expressed by neuroblastoma it remains to be established as to whether also glioblastomas cells are endowed with this property. We have addressed this issue using the human continuous glioblastoma cell line ADF. We demonstrated that these cells possess tyrosinase as well as L-tyrosine hydroxylase (TH) activity and synthesize melanosomes. Because the two pathways are potentially cyto-genotoxic due to production of quinones, semiquinones, and reactive oxygen species (ROS), we have also investigated the expression of the peroxisomal proliferators activated receptor alpha (PPARalpha) and nuclear factor-kB (NFkB) transcription factor as well the effect of L-tyrosine concentration on cell survival. We report that L-tyrosine down-regulates PPARalpha expression in ADF cells but not neuroblastoma and that this aminoacid and phenylthiourea (PTU) induces apoptosis in glioblastoma and neuroblastoma.
The effect of phenylthiourea (PTU) on the pigment epithelium and the photoreceptor cells in the developing retina of Haplochromis burtoni was studied by electron microscopy. In the retinal pigment epithelium of 6-day old embryos, both types of melanin granule (spindle-shaped and rod-shaped) are already found. PTU inhibits the biosynthesis of melanin but does not influence the formation of premelanosomes so that in PTU-treated embryos there are no melanosomes, but an abundance of premelanosomes. The structure of the premelanosomes is described. It differs completely from that of all other vertebrates. Other changes: an increase in polysomes, retarded development of the inner segment of the photoreceptor cells and enlargement of the intercellular space between the inner and outer leaflet of the retina, may be due to a toxic effect of PTU.
1-(5-Aminopentyl)-3-phenylthiourea (PPTU), a recently developed inhibitor of the transglutaminase-catalyzed reaction (K.N. Lee, L. Fesus, S.T. Yancey, J.E. Girard, and S.I. Chung, (1985) J. Biol. Chem. 260, 14689-14694) was evaluated as a possible probe to examine the physiological role of transglutaminase (EC 2.3.2.13) in Chinese hamster ovary (CHO) cells. The [14C]PPTU in cell culture was readily taken up by CHO cells and was found to be covalently attached to high-molecular-weight proteins which are associated with the particulate fractions. Incubating cell homogenates, in the presence of Ca2+, incorporated the labeled PPTU exclusively into high-molecular-weight proteins that were also undergoing polymerization. PPTU at 0.1 mM, a concentration close to the Ki value reported for inhibition of tissue transglutaminase-catalyzed amine incorporation into the B chain of oxidized insulin, decreased high-molecular-weight protein polymerization, whereas PPTU at the same concentrations showed no effect on CHO cell proliferation or on in vitro calmodulin activation of cyclic nucleotide phosphodiesterase. These results suggest that transglutaminase may not be a constitutive enzyme in cell proliferation.
A series of 1-hydroxyalkyl-3-phenylthiourea analogs were prepared and evaluated as HDL-and Apo A-I-elevating agents. Derivatives 5h, 7j, 7n, and 7o were found to be as effective or superior to gemfibrozil.
A series of 1-alkyl-3-phenylthiourea analogues were prepared and evaluated as HDL- and Apo A-I-elevating and triglyceride-lowering agents. Several derivatives were superior to gemfibrozil. The optimal analogue (HDL376) was shown to raise HDL cholesterol in the rat, hamster, dog, and monkey models.
It was previously found that L-tyrosine oxidation product(s) are cytotoxic, genotoxic and increase the sister chromatid exchange (SCE) levels in human melanoma cells. In this work, the micronucleus assay has been performed on human melanotic and amelanotic melanoma cell lines (Carl-1 MEL and AMEL) in the presence of 1.0, 0.5 and 0.1 mM L-tyrosine concentrations to investigate if melanin synthesis intermediate(s) increase micronuclei production. L-Tyrosine oxidation product(s) increased the frequency of micronuclei in melanoma cells; 0.1 mM phenylthiourea (PTU), an inhibitor of L-tyrosine oxidation by tyrosinase, lowered the micronucleus production to the control levels. The culture of melanoma cells with high L-tyrosine in the culture medium resulted in a positive response to an ELISA-based apoptotic test. For comparison the effect of L-tyrosine on micronuclei production in human amelanotic melanoma cells was also investigated; the micronucleus production in the presence of 1 mM L-tyrosine in the culture medium was lower than that found with melanotic melanoma cells of the same cell line. The data suggest that melanin synthesis intermediates arising from L-tyrosine oxidation may cause micronuclei production in Carl-1 human melanoma cells; the addition of PTU in the presence of L-tyrosine decreased the frequency of micronuclei to about the control values thus the inhibition of melanogenesis may have some clinical implication in melanotic melanoma.
Mice from 25 laboratory strains were given the choice of drinking a dilute (100 mg/litre) solution of phenylthiourea (PTC) or a control solution containing no PTC. The consumption of PTC by each strain was measured daily over a period of 10 days. There was considerable variation between strains in their consumption of PTC. The mean PTC consumption of the 13 albino strains was less than the mean of the 12 pigmented strains. Most strains showed a decrease in PTC consumption during the 10 days of the experiment and the albino strains showed, on average, a greater decrease than did the pigmented strains. Tests with congenic strains proved that the albino allele itself is not the cause of the reduced PTC consumption. The possibility of a gene which is linked to the albino locus and which has an effect on PTC consumption is discussed.
Tyrosinase, the rate-limiting enzyme of melanin synthesis, is a di-copper metalloprotein that catalyzes the conversion of L-tyrosine to L-DOPAquinone. Phenylthiourea (PTU) is a well-known inhibitor of tyrosinase and melanin synthesis and is known to interact with sweet potato catechol oxidase, an enzyme possessing copper binding domain homology to tyrosinase. While PTU is frequently used to induce hypopigmentation in biological systems, little is known about its effects on tyrosinase and other melanogenic proteins. We have found that PTU induces degradation of tyrosinase but not of other melanogenic proteins including the tyrosinase-related metalloproteins tyrosinase-related protein (Tyrp)1 and Tyrp2. Using pulse-chase analysis coupled with glycosidase digestion, we observed that tyrosinase degradation occurs following complete maturation of the protein and that degradation was reversed by cysteine protease inhibitor E64 but not proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal. We conclude that PTU specifically induces tyrosinse degradation following Golgi maturation. Our data suggest that in addition to well-known ER-directed quality control, tyrosinase is also subject to post-Golgi quality control.
Taste thresholds for phenylthiourea were measured for 244 Ashkenazic Jews. The frequency of nontasters was 27.86 percent. In the sample, 102 individuals were of pure Polish ancestry, and the frequency of nontasters among these was significantly different from the frequencies of nontasters among Europeans and Mongoloids.
Phenylthiourea (PTC) taste sensitivity thresholds have been measured for 2,013 Nigerians using a modified sorting technique. The frequency of non-tasters was observed to be 12.5% and the t gene frequency was 0.354. There was a significant difference between the sexes at the 0.01 level for the overall population. However, when the data are analyzed according to the geographical origin of the subject, the sex difference is found only in one of three geographical regions. Also, there may be geographical influences on PTC taste sensitivity, although this was not statistically significant. The estimates reported in this population differ considerably from some of the previously published estimates for black populations.
A series of phenylthiourea and ethylthiourea derivatives of daunorubicin and its congeners was prepared by reaction of the 3'-amino group of the antibiotic with phenylisothiocyanate or ethylisothiocyanate. S-Methylation yielded S-methylisothiouromium salts which when reacted with amines resulted in an intramolecular cyclization with the participation of the neighboring 4'-OH group. The structures and predominant conformations of the thiourea derivatives and daunorubicino(3'-N,4'-O-d)oxazolines were determined by 1H and 13C NMR. Cytostatic activities of the thiourea and oxazoline derivatives were compared with the cytostatic activities of N-methylurea and N-methyl-N-nitrosourea containing daunorubicin and its congeners. Carminomycin derivatives were endowed with the highest cytostatic activity.
Isoproterenol inhalation increases the pulmonary edema induced in rats by phenylthiourea. Propranolol decreases this response while phenoxybenzamine has no effect upon it. It is proposed that the observed increase in toxicity is related to the beta-adrenergic effects of the isoproterenol and that the specific mechanism responsible might be an increase in pulmonary capillary hydrostatic pressure which is secondary to an increase in pulmonary blood flow.