The effects of various substituted hydrocarbons on two heme synthesis regulatory enzymes

Benzene and some of its derivatives have been shown to cause alterations in heme and globin synthesis. Structure/activity relationships of the effects of substituted aromatic hydrocarbons on delta-aminolevulinic acid synthetase (ALAS) and ferrochelatase (FC) activities were studied. These enzyme systems were studied because they were regulatory and represented the initial and final enzymes in the biosynthesis of heme. Normal values for rat liver ALAS were 250-350 microM ALA/g protein/30 min, mean 293 microM/g +/- 44 (SD). Normal values for FC were 12-40 microM heme/g protein/45 min, mean 18 microM/g +/- 0.7 (SD). Nitrosonaphtholics inhibited ALAS activity an average of 49%; nitrosobenzenes, 48%; chloronitrobenzoic acids, 39%; phenol, 37%; nitrophenols, 22%; aminophenols, 16% and chlorophenols, 5%. Certain compounds inhibited FC activity: nitrosonaphtholics, 99%; chlorophenols, 56% and nitrosobenzenes, 3%. Some compounds that significantly inhibited ALAS activity enhanced FC activity, e.g. phenolic compounds and chloronitrobenzoic acids. The inhibitory effect may reflect a blockage of the active site of the enzymes and/or binding of a required substrate. The enhancing effect may be due to making the binding site of the heme pocket of the porphyrin more accessible to iron. These techniques may prove useful for assessing toxicity of pollutants in animal species.