Epigenetic activation of the 5-hydroxytryptamine (serotonin) receptor 2C in embryonal carcinoma cells is DNA replication-dependent

The epigenetic states of key regulatory genes must be altered to drive cell fate decisions in differentiating cells. This process must be coupled, at least transiently, to the DNA replication machinery. Only a few genes, however, have been shown to require DNA replication for their activation or repression upon induction of differentiation. We have developed a methodology for examining how gene expression is coupled to cell division during the early stages of differentiation of embryonal carcinoma (EC) cells. Using this approach, we find that the expression of the 5-hydroxytryptamine (serotonin) receptor 2C (Htr2c) is strongly increased in the second division after all-trans retinoic acid addition. We propose that the epigenetic activation of Htr2c in EC cells results from a chromatin remodeling process that requires at least two passages through S phase.     

Bupivacaine, but not lidocaine, disrupts cardiolipin-containing small biomimetic unilamellar liposomes

Inadvertent intravenous administration of bupivacaine, unlike that of lidocaine, is associated with significant cardiotoxicity. However, the mechanism(s) underlying this phenomenon is uncertain. High concentrations of cardiolipin, an anionic phospholipid, are found in the mitochondria membrane of cardiomyocytes. We hypothesized that bupivacaine, but not lidocaine, interacts avidly with cardiolipin in the mitochondria membrane of cardiomyocytes and alters its integrity thereby accounting, in part, for cardiotoxicity. Accordingly, the purpose of this study was to begin to address this issue by determining the effects of bupivacaine and lidocaine on permeability of cardiolipin-containing biomimetic small unilamellar liposomes. We found that bupivacaine, but not lidocaine, elicited a significant, concentration-dependent increase in carboxyfluorescein release from cardiolipin-containing small unilamellar liposomes (size, 165 nm) composed of egg yolk phosphatidylcholine and cholesterol (p < 0.05). Both drugs had no significant effects on carboxyfluorescein release from liposomes devoid of cardiolipin (p > 0.5). Collectively, these data indicate that bupivacaine, but not lidocaine, interacts avidly and selectively with biomimetic small unilamellar liposomes containing cardiolipin and disrupts their integrity. We suggest that these interactions underlie, in part, bupivacaine-induced cardiotoxicity.