Liposome dependent delivery of S-adenosyl methionine to cells by liposomes: a potential treatment for liver disease.
The present study demonstrates that the nutritional supplement S-adenosyl methionine (SAMe), the primary methyl donor in mammalian cells, is delivered selectively to cells by anionic liposomes, and is, therefore, a liposome dependent drug. Contrary to our expectations, free SAMe chloride was growth inhibitory in cultured cells. The growth inhibitory potency of SAMe chloride in anionic liposomes composed of distearoylphosphatidylglycerol/cholesterol 2:1 was fivefold greater than that of free SAMe. Neutral liposomes composed of distearoylphosphatidylcholine and cholesterol did not increase the potency of the drug. An improved anionic liposome SAMe formulation was produced by use of the 1,4-butanedisulfonate salt (SD4), adding a metal chelator (EDTA), and lowering the buffer pH from pH 7.0 to pH 4.0. This formulation was 15-fold more potent than free SD4, and was active after more than 28 days at 4 degrees C. SAMe and its potential degradation products were screened for toxicity. Formaldehyde was determined to have potency similar to that of free SAMe chloride in CV1-P cells, suggesting that the growth inhibitory effects of SAMe may partly arise from the formation of formaldehyde. The cytotoxic effects of formaldehyde and the less stable forms of SAMe, (SAMe chloride and SAMe tosylate) were decreased in the presence of 3 mM GSH (IC(50) approximately 0.44 mM). The cytotoxic effects of SD4 were not reduced by GSH, suggesting that this more stable form of SAMe is not toxic through the production of formaldehyde. SD4 in anionic DSPG liposomes stimulated murine IL-6 production in RAW 264 cells at concentrations 25- to 30-fold lower than free drug. This increase in potency for IL-6 production was in keeping with the increase in potency observed in our growth inhibition experiments. These results suggest that SD4 in liposomes may be a potential treatment for acute or chronic liver failure.
Wagner
Eric J
EJ
Schools of Pharmacy and Veterinary Medicine, University of Wisconsin Madison, Madison, Wisconsin 53705-222, USA.
Krugner-Higby
Lisa
L
Heath
Timothy D
TD
D000476:Alkanesulfonates / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects*; D002614:Chelating Agents / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004355:Drug Stability; D004492:Edetic Acid / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D015850:Interleukin-6 / Q000378:metabolism; D008081:Liposomes; D017093:Liver Failure / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D010715:Phosphatidylglycerols / Q000737:chemistry*; D020011:Protective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D012436:S-Adenosylmethionine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D000476:Alkanesulfonates; D002614:Chelating Agents; D015850:Interleukin-6; D008081:Liposomes; D010715:Phosphatidylglycerols; D020011:Protective Agents; C092739:1,4-butanedisulfonate; C084352:distearoyl phosphatidylglycerol; D012436:S-Adenosylmethionine; D002784:Cholesterol; D004492:Edetic Acid