The Influence of Antagonists of Poly(Adp-Ribose)Polymerase on the Activity Of Antirheumatic Drugs on the Development of Adjuvant Arthritis in Rats and on the Induction of Tyrosine Aminotransferase in the Liver of Rats

Poly-adenoribosylation is a posttranslational modification of chromatin-bound proteins. Recently, there has been increasing evidence that poly-adenoribosylation is involved in the genesis of cancer but also in the genesis of autoimmune diseases such as rheumatoid arthritis. The synthesis of poly(ADP-ribose) by the enzyme poly(ADP-ribose)polymerase depends on the intracellular levels of NAD and this depends on the supply with the precursers tryptophan, nicotinamide, and nicotinic acid. Poly-adenoribosylation is a protective cellular response to DNA damage which leads to a decrease in the NAD content of cells (Kroger et al., 1960). The consequence is a depletion of NAD with a reduced poly(ADP-ribose) accumulation and altered biological responses such as the expression of disease specific genes (Jacobson et al., 1992, Ehrlich, et. al., 1995). The question has been raised whether agents or conditions that influence the NAD-poly(ADP-ribose)metabolism do have an effect on the pathogenesis of diseases such as rheumatoid arthritis. Previously, we reported that a combination of benzamide or a diet without tryptophan and nicotinamide in combination with D-penicillamine leads to an improvement of adjuvant arthritis in rats (Kroger and Ehrlich, 1994). We continued these studies and investigated the effects of the poly(ADP-ri- bose)polymerase antagonists nicotinamide, benzamide, caffeine-derivatives and a diet lacking tryptophan and nicotinamide alone and in combination with the antirheumatic drugs endoxan (cyclophosphamide), D-penicillamine, auranofin, voltaren, and methotrexate on the development of adjuvant arthritis of rats. In another set of experiments we studied the influence of D-penicillamine, benzamide, and cofpropamine (a caffeine-derivative) on the induction of tyrosine aminotransferase in the liver of rats with adjuvant arthritis set on a diet without tryptophan and nicotinamide.