Abstract
The effects of in vitro treatment of the hepatic microsomal fraction with various porphyrin compounds on the activity and the content of the heme-containing components of the mixed function oxidase system were studied. The compounds examined were hematin, methemalbumin (with heme to protein molar ratio of 13:1 or 1:1), mesohemalbumin, bilirubin, biliverdin, mesoporphyrin IX, and protoprophyrin IX. The activity of the system was monitored by measuring its oxidative activity for the type I and type II substrates, ethylmorphine and aniline, respectively; as well as the microsomal contents of cytochrome P-450 and b5 and 14C-labeled heme, Mesoporphyrin IX was found to be most effective in inhibiting the oxidative activity of the mixed function oxidase system as well as in decreasing the microsomal contents of cytochromes P-450, b5, and heme. Biliverdin exerted no effect on these parameters. Hematin and the other compounds studied exerted variable inhibitory effects on the system. The degradative and inhibitory effects of protoporphvrin IX and mesoporphyrin IS could be blocked significantly by conducting the studies in the dark. The presence of biliverdin decreased the inhibitory effects of the porphyrins on the system; conversely the effects could be magnified in the presence of deuterium oxide. It is suggested that the mechanism by which porphyrins inhibit the mixed function oxidase system is through porphyrin-sensitized photo-oxidation of various constituents of the hepatic microsomal fraction and that the formation of singlet oxygen molecules is most likely involved in this process. Moreover the destructive effects of heme compounds on the microsomal components and activities of the drug-metabolizing mixed function oxidase system raise questions concerning the hypothesis that the components of this system, and specifically cytochrome P-450, are involved in the activity of the heme oxygenase system.
Highlights
The effects of in vitro treatment of the hepatic microsomal fraction with various porphyrin compounds on the activity and the content of the heme-containing components of the mixed function oxidase system were studied
Since the components of the hepatic microsomal mixed function oxidase system which oxidizes drugs [12], as well as metalloporphyrin compounds such as hematin, methemalbumin, mesohemin etc. [13, 14], are associated with or are part of the membranes of the endoplasmic reticulum, this study was undertaken to investigate the effects of various porphyrins on the activity and the components of this system
System-Table I shows the effect of treatment of microsomal fractions (1.5 to 2.5 mg of protein/ml, at 37” for 30 min, under atmosphere, in light) with methemalbumin and mesohemalbumin, at final concentrations of 17 and 34 pM
Summary
The effects of in vitro treatment of the hepatic microsomal fraction with various porphyrin compounds on the activity and the content of the heme-containing components of the mixed function oxidase system were studied. Mesoporphyrin IX was found to be most effective in inhibiting the oxidative activity of the mixed function oxidase system as well as in decreasing the microsomal contents of cytochromes P-450, b,, and heme. Pounds have a relatively low water solubility, they exist closely associated with biological membranes and form complexes with various components of the membranous proteins [11] In this complexed form the porphyrins and the metalloporphyrins are photoexcitable and are capable of inflicting photodynamic damage to the membrane structures. The results of the study indicate that certain of these compounds greatly damage the components and functional integrity of this enzyme complex
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