Cytokinetic studies reveal etiology of cytogenetic genotoxicity produced by a series of angiotensin II (AII) receptor antagonists may be perturbed DNA synthesis

• Published in: Cytometry (Baltimore); (United States) Vol. 6
• Main Authors: Selden, J.R., Miller, J.E., Dolbeare, F., Galloway, S.M., Nichols, W.W.
• Format: Conference Proceeding
• Language: English
• Published: United States 01.01.1993
• Subjects: 550200 > Biochemistry; ANGIOTENSIN; BASIC BIOLOGICAL SCIENCES; BIOSYNTHESIS; CARDIOVASCULAR AGENTS; CELL CYCLE; CELL DIVISION; CHROMOSOMAL ABERRATIONS; CYTOLOGICAL TECHNIQUES; DNA; DNA REPLICATION; DRUGS; GLOBULINS; INHIBITION; MEMBRANE PROTEINS; MUTATIONS; NUCLEIC ACID REPLICATION; NUCLEIC ACIDS; ORGANIC COMPOUNDS; PROTEINS; RECEPTORS; SYNTHESIS; VASOCONSTRICTORS 550300 > Cytology
• ISSN: 0196-4763; 1097-0320

Six of 13 AII receptor antagonists produced chromosomal aberrations in CHO cells. In addition, these six compounds perturbed cellular kinetics (i.e., reduced mitotic indices and cell yields). It was hypothesized that the mechanism of clastogenesis was not due to a direct genotoxic effect, but may result from disruption of DNA replication. Flow cytokinetic studies, using the BrdUrd-FITC/propidium iodide technique, were performed on all six clastogenic compounds, and a seventh candidate from this group. All seven altered CHO cell kinetics as follows: (1) The amount of BrdUrd per S phase cell was reduced; (2) Cell movement within S phase was inhibited; and (3) Lowest doses perturbing CHO cell kinetics were below minimum concentrations producing aberrations. These data provide evidence that this cytogenetic damage is mediated by a mechanism which disrupts cellular DNA synthesis.