PubMed · 14418744
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H LUEERS. 1960-03-10. [Mutation experiments withmegaphen].. https://pubmed.ncbi.nlm.nih.gov/14418744/
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BACKGROUND: Deposits in the cornea and lens are a known complication of long-term chlorpromazine therapy. METHOD: A 59-year-old woman had previously taken chlorpromazine for 20 years with doses up to 1,200 mg/day, with a mean dose of 400 mg/day. She presented with gradual onset of blurred vision in her left eye. Slit-lamp biomicroscopy revealed multiple fine creamy-white deposits on her corneal endothelium and anterior crystalline lens capsule bilaterally. RESULTS: In vivo confocal microscopy of the cornea identified irregular hyper-reflective deposits on the posterior surface of the endothelium. The deposits varied from 1 microm to 70 microm in diameter and had well-defined edges. Endothelial morphology was otherwise normal bilaterally. CONCLUSIONS: This is the first report of in vivo confocal imaging of deposits resulting from long-term chlorpromazine use. Microstructural analysis of the corneal endothelium reveals that there were no abnormalities in cellular morphology resulting from these deposits.
To assess the affinity of psychotropic phenothiazine drugs, triflupromazine (TFZ) and chlorpromazine (CPZ), for the membranes of central nervous system and the other organs in the body, the partition coefficients (Kps) of these drugs to phosphatidylcholine (PC)-phosphatidylserine (PS) and PC-phosphatidylethanolamine (PE) small and large unilamellar vesicles (SUV, LUV) were examined by a second-derivative spectrophotometric method, since PS is abundantly contained in the membranes of the central nervous system and PE is distributed widely in the membranes of the organs in the body. Size and preparation methods of the vesicles did not affect the Kp values at each aminophospholipid content suggesting that the partition of the phenothiazine drugs was not affected by the structural differences in the vesicles such as their curvature or asymmetric distribution of the phospholipids between the outer and inner layers of the bilayer membranes. However, the Kp values of both drugs increased remarkably according to the PS content in the bilayer membranes, i.e., the Kp values for the vesicles of 30 mol% PS content were about 3 times of that for the vesicles of PC alone, while both Kp values slightly reduced with the increase in the content of PE in the bilayer membranes of PC-PE vesicles. The results indicate that both drugs have higher affinity for the PC-PS bilayer membranes than for the PC and PC-PE membranes, which can offer an evidence for the fact that TFZ and CPZ are predominantly distributed and accumulated in the brain and nerve cell membranes that contain PS abundantly.
In Saccharomyces cerevisiae, Maf1 is essential for mediating the repression of transcription by RNA polymerase (pol) III in response to diverse cellular conditions. These conditions activate distinct signaling pathways that converge at or above Maf1. Thus, Maf1-dependent repression is thought to involve a common set of downstream inhibitory effects on the pol III machinery. Here we provide support for this view and define two steps in Maf1-dependent transcriptional repression. We show that chlorpromazine (CPZ)-induced repression of pol III transcription is achieved by inhibiting de novo assembly of transcription factor (TF) IIIB onto DNA as well as the recruitment of pol III to preassembled TFIIIB.DNA complexes. Additionally Brf1 was identified as a target of repression in extracts of CPZ-treated cells. Maf1-Brf1 and Maf1-pol III interactions were implicated in the inhibition of TFIIIB.DNA complex assembly and polymerase recruitment by recombinant Maf1. Co-immunoprecipitation experiments confirmed these interactions in yeast extracts and demonstrated that Maf1 does not differentially sequester Brf1 or pol III under repressing conditions. The results suggest that Maf1 functions by a non-stoichiometric mechanism to repress pol III transcription.