Inhibitory Effects of Pteridines on the Cytochrome P-450 Enzyme System

Abstract

The effects of 17 different pteridine derivatives on rat liver microsomal cytochrome P-450 catalyzed degradation of aminoantipyrin were studied. Neopterin (41% of control), biopterin (42%), monapterin (73%), pterin (74%), lumazine (75%) and 6-methylpterin (77%) significantly inhibit the degradation of aminoantipyrin. 6,7-Dimethylpterin (80%) and 6-hydroxymethylpterin (89%) show weak but non-significant effects, and the remaining pteridine derivatives investigated (pterin-6-carboxylate, pterin-7 -carboxylate, pterin-6-aldehyde, 7,8-dihydro-neopterin, 7,8-dihydro-biopterin, sepiapterin, xanthopterin, isoxanthopterin, and leukopterin ) do not interact with the enzyme system. In addition, spectroscopic investigations were performed for colourless pteridine derivatives. Neopterin, biopterin, monapterin and pterin yielded type II binding spectra, indicating their binding to the heme iron of the active center of the enzyme. In agreement with the inhibition studies, 7,8-dihydroneopterin and 7,8-dihydrobiopterin did not exhibit spectroscopic evidence tor their interaction with the enzyme system. When attempting to correlate structural features of the pteridine compounds with their effect on the cytochrome P450 system, presence of a hydroxy function at C2 of an alkyl sidechain at C6 of the ring system was found to be particularly important for inhibition of aminoantipyrin degradation, while a 7,8-dihydro structure has the opposite effect. Interestingly, pteridines strongly interacting \vith the cytochrome P450 system also cause strong enhancement of radical-induced luminol-dependent chemiluminescence and of the growth-inhibitory potential of radical-yielding disinfectants towards bacteria, ·while 7,8-dihydropteridines in these other experimental systems show strong scavenger activity.

Keywords

• cytochrome p -450
• rat liver microsomes
• pteridine derivatives
• molecular structure
• aminoantipyrin degradation