PubMed Health⌕ Search

Biomedical subjects

P Huart

Publications and source records attributed to P Huart.

6 recordsLinked to original sources
PubMed1990

Structure of the adriamycin-cardiolipin complex. Role in mitochondrial toxicity.

Adriamycin and its derivatives are among the most efficient antimitotics used in clinical therapy. A specific cardiotoxicity places a limit on the total dose of adriamycin that may be administered. The mechanism of cardiac toxicity is complex. Data accumulated from in vitro and in vivo studies indicate a possible common cause for the inhibition of numerous enzymes and tissue degradation by a free radical mechanism: the binding of adriamycin to the inner mitochondrial membrane cardiolipin. The structure of the adriamycin-cardiolipin complex has been investigated by using physico-chemical techniques and via conformational analysis. The results open a rational way to design new structures that are less cardiotoxic.

Animals↗
PubMed1988

A comparative model membrane study on structural effects of membrane-active positively charged anti-tumor drugs.

The interaction of a number of positively charged anti-tumor drugs with cardiolipin-containing model membranes has been investigated using 31P nuclear magnetic resonance (31P-NMR), differential scanning calorimetry (DSC) and monolayer techniques. It appeared that the ellipticines used (i.e., celiptium and 2-N-methylellipticinium), and also ethidium bromide, completely blocked Ca2+-induced HII phase formation in pure cardiolipin liposomes at molar ratios of drug-to-lipid of approx. 1:1. For the anthracyclines adriamycin and 4'-epi-adriamycin, a similar effect was observed, but now a 2:1 ratio was required. 31P-NMR experiments on dioleoylphosphatidylethanolamine/cardiolipin mixed liposomes indicated that the two anthracyclines, but not the other three drugs, were capable of inducing macroscopic phase separation into domains enriched in drug-cardiolipin complexes and domains enriched in the zwitterionic phospholipid species. DSC experiments on dipalmitoylphosphatidylcholine/cardiolipin mixtures led, with the exception of 2-N-methylellipticinium, to the same conclusion. Measurements of surface pressure and surface potential of cardiolipin monolayers at the air/water interface as well as conformational analysis of the various drug-cardiolipin recombinants showed that the ellipticines are deeply embedded in the acyl chain region of the bilayer, while the anthracyclines and ethidium bromide are preferentially localized in the interface. All drugs share an important electrostatic interaction with the negatively charged phosphates of cardiolipin.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1987

Study of the adriamycin-cardiolipin complex structure using attenuated total reflection infrared spectroscopy.

Adriamycin plays a prominent role in the treatment of leukemia and solid tumors in man. The mode of interaction of adriamycin with its nuclear target, responsible for its therapeutic effect, is known [Berman, H. M., & Young, P.R. (1981) Annu. Rev. Biophys. Bioeng. 10, 87-114]. The planar anthracycline moiety of adriamycin intercalates between the base pairs whereas the sugar moiety fits into the DNA large groove. However, the cardiotoxicity of adriamycin places a limit on the total dose that may be given [Minow, R. A., Banjamin, R.S., & Gottlieb, J. A. (1975) Cancer Chemother. Rep. 6, 195-202]. Much evidence suggests that the mitochondrial membrane could be the target responsible for adriamycin cardiotoxicity. The formation of a very stable complex between adriamycin and cardiolipin, a phospholipid specific to the inner mitochondrial membrane, has been shown to inhibit several mitochondrial membrane enzymes whose activities depend on the presence of cardiolipin. Using attenuated total reflection infrared spectroscopy, we demonstrate here that, in the adriamycin-cardiolipin complex, both cardiolipin and adriamycin structures are modified as compared with the pure substances. Dichroism values indicate a slight reorientation of the cardiolipin molecule toward a normal to the plane of the bilayer whereas adriamycin, which shows no ordering in a pure phase, is highly ordered in the complex, the anthracycline moiety titled at about 40 degrees with respect to the normal to the plane of the bilayer. The partial disappearance of NH3+ characteristic bands indicates the involvement of the positively charged amino group of adriamycin in the complex formation.

Ammonia↗
PubMed1986

Mechanism of inhibition of mitochondrial enzymatic complex I-III by adriamycin derivatives.

We demonstrate here that complex I-III of bovine heart mitochondrial membrane is inhibited by adriamycin derivatives. This inhibition is a cardiolipin-dependent process. This lipid, specific to the inner mitochondrial membrane, has been shown previously to interact specifically with adriamycin in model membranes (Goormaghtigh, E., Chatelain, P., Caspers, J. and Ruysschaert, J.-M. (1980) Biochim. Biophys. Acta 597, 1-14) and in mitochondrial membranes (Cheneval, D., Müller, M., Toni, R., Ruetz, S. and Carafoli, E. (1985) J. Biol. Chem. 260, 13003-13007). The differential scanning calorimetry data indicate that, in multilamellar liposomes, the formation of antibiotic-cardiolipin complexes induces a clustering of cardiolipin molecules. Conformational analysis of the antibiotic-cardiolipin complexes suggests that plane-plane interactions between the antibiotics aromatic moieties stabilize this complex formation. Possible mechanisms of inactivation of complex I-III by adriamycin are proposed.

Animals↗
PubMed1985

Structural analogies between protein kinase C activators.

Phorbol esters and diacylglycerols activate protein kinase C but specific structural parameters appear to be required for the enzyme activation. We have analyzed the conformation of potent and not potent diacylglycerols and phorbol esters. The orientation of the CH20H group at C3 of 1,2 diolein is remarkably similar to that of the same group at C-20 of 4 beta phorbol didecanoate and crucial for potency in activating the enzyme. Our data suggest that the new conformational approach here described could be used to rationally design specific inhibitors preventing the effects of tumor promoters and to predict the structure of potential tumor promoters.

Acetylation↗