Pyridinedicarboxylates, the first mechanism-derived inhibitors for prolyl 4-hydroxylase, selectively suppress cellular hydroxyprolyl biosynthesis. Decrease in interstitial collagen and Clq secretion in cell culture.
Two pyridinedicarboxylates, predicted [Hanauske-Abel (1983) M.D.-Ph.D. Thesis, Philipps Universität Marburg] and later found to be potent reversible inhibitors of purified prolyl 4-hydroxylase [Majaama, Hanauske-Abel, Günzler & Kivirikko (1984) Eur. J. Biochem. 138, 239-245] were investigated with respect to their effect on hydroxyprolyl biosynthesis in the fibroblast/collagen and the macrophage/Clq systems, and the effect was compared with that of the iron chelator 2,2'-dipyridyl, the compound usually employed to inhibit cellular hydroxyprolyl formation. Only the enzyme-mechanism-derived pyridinedicarboxylates were highly selective inhibitors, and only they lacked overt cytotoxicity. Morphologically, their effect was restricted to the site of cellular hydroxyprolyl biosynthesis, i.e. the cisternae of the rough-surfaced endoplasmic reticulum. They were equally effective in the different cell types studied, and human and guinea-pig fibroblasts showed the same sensitivity. The minimal lipophilicity of the pyridinedicarboxylates necessitated high concentrations to achieve suppression of cellular hydroxyprolyl formation, but lipophilic bio-activatable pro-inhibitors may overcome this disadvantage. For the first time, experimental evidence is presented suggesting that, in cell culture, the biosynthesis of interstitial collagens and Clq can be suppressed selectively, identifying the pyridinedicarboxylates as promising pilot compounds for experiments in vivo.
Tschank
G
G
Institute of Toxicology, Johannes Gutenberg University, Mainz, Federal Republic of Germany.
Raghunath
M
M
Günzler
V
V
Hanauske-Abel
H M
HM
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003166:Complement Activating Enzymes / Q000378:metabolism; D003172:Complement C1 / Q000378:metabolism; D015922:Complement C1q; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006168:Guinea Pigs; D006801:Humans; D006909:Hydroxyproline / Q000096:biosynthesis*; D008854:Microscopy, Electron; D010848:Picolinic Acids / Q000494:pharmacology*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*
D003172:Complement C1; D010848:Picolinic Acids; D015922:Complement C1q; D003094:Collagen; D011393:Procollagen-Proline Dioxygenase; D003166:Complement Activating Enzymes; D006909:Hydroxyproline; C004860:dipicolinic acid