Current Papers in Liver Disease - February, 1999

By Howard J. Worman, M. D.
Columbia University

This is a past issue of Current Papers in Liver Disease.

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Odaib, A. A., Shneider, B. L., Bennett, M. J., Pober, B. R., Reyes-Mugica, M., Friedman, A. L., Suchy, F. J., and Rinaldo, P. 1998. A defect in the transport of long-chain fatty acids associated with actue liver failure. New England Journal of Medicine. 339:1753-1757.

Individuals with a variety of disorders of fatty acid metabolism have liver, heart or skeletal muscle abnormalities. This paper describes two case reports of young boys who presented with acute liver failure and were found to have a defect in the cellular uptake of long-chain fatty acids. Cells isolated from the patients were defective in the oxidation of long-chain fatty acids. However, treatment of cells with the detergent digitonin, which allows fatty acids to traverse the cell membrane, restored their ability to oxidize fatty acids. These two case reports suggest that cellular defects in the uptake of fatty acids can cause acute liver failure. The genetic defects responsible for abnormal fatty acid uptake in these cases remain to be determined.

Xiong, X., Flores, C., Yang, H., Toole, J. J., and Gibbs, C. S. 1998. Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro. Hepatology. 28:1669-1673.

In December 1998, the United States Food and Drug Administration approved lamivudine for the treatment of hepatitis B. Lamivudine in a nucleoside analogue that inhibits the activity of the hepatitis B virus (HBV) DNA polymerase. However, about 10% to 20% of patients treated with lamivudine develop resistance to the drug as a result of mutations in the HBV DNA polymerase. In this study, the authors show that polymerase mutants that are resistant to lamivudine are not resistant to adefovir, an experimental polymerase inhibitor currently in clinical trials, in an experimental assay. These results suggest that adefovir may be someday be used in combination with lamivudine or as an "add on" drug if resistance to lamivudine develops.

Huang, H., Chopra, R., Verdine, G. L., and Harrison, S. C. 1998. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science. 282:1669-1675.

HIV-1 uses an enzyme known as reverse transcriptase to replicate it genome. Hepatitis B virus (HBV) uses an enzyme known as DNA polymerase to replicate its genome. Although there are differences, these two enzymes are common in several ways. For one, they both "copy" a single DNA strand into a complementary strand. Perhaps the most important similarity from a clinical perspective is that both enzymes are inhibited by some of the same drugs known as nucleoside analogues, examples being lamivudine (3TC) and adefovir. In this study, the authors used sophisticated chemical methods to trap the HIV-1 reverse transcriptase stalled in action. They were able to make crystals of HIV-1 reverse transcriptase complexed to DNA and in the act of adding a deoxynucleoside triphosphate to the new DNA strand. They were then able to determine the molecular structure of this complex by X-ray crystallography. Analysis of this structure provides important insights into the mechanisms of action of nucleoside analogues and how mutations in the enzyme lead to resistance to these compounds (for the relevance to HBV, see the paper by Xiong et al. reviewed immediately above this one). These results will allow pharmaceutical chemists to make novel compounds that inhibit HIV-1 reverse transcriptase that may also inhibit HBV DNA polymerase. In addition, the same methods can theoretically be used to obtain a snapshot of the HBV DNA polymerase in action.

Copyright, 1999, Howard J. Worman, M. D. All rights reserved. Printing or other reproduction is prohibited without the written authorization of Howard J. Worman.