Sulfonamide inhibition of rat hepatic uroporphyrinogen I synthetase activity and the biosynthesis of heme

Abstract

Sulfonamides are known to provoke attacks of acute intermittent porphyria, which is characterized by a deficiency of uroporphyrinogen I synthetase (EC 4.3.1.8) activity. Various sulfonamides were examined for their potential as inhibitors of purified rat hepatic uroporphyrinogen I synthetase activity in vitro, and 10 were found to be inhibitory. Inhibition of uroporphyrinogen I synthetase activity by sulfonamides is reversible by dialysis and exhibits noncompetitive kinetics. Inhibition constants ( K i ) ranged from 100 μ m for sulfaguanidine to 270 μ m for sulfadiazine. These observations were extended to in vivo studies using sulfamerazine ( K i = 250 μm). Twenty-four hours after administration of sulfamerazine (orally; 1 g/kg) to male rats, hepatic microsomal heme and cytochrome P-450 contents were decreased approximately 33 and 42%, respectively. This was reflected by the inhibition of both aniline- p-hydroxylase and amino pyrine- N-demethylase activities, which are P-450 mediated. Heme oxygenase activity was not altered by sulfamerazine treatment. However, the relative rate of heme biosynthesis, as measured by the incorporation of δ-[4- 14C]aminolevulinic acid into heme, was 28% lower in sulfamerazine-treated rats. Thus, these results indicate that sulfamerazine acts to inhibit heme biosynthesis. Hepatic δ-aminolevulinic acid synthetase (EC 2.3.1.37) activity was increased 2.2-fold in the sulfamerazine-treated group, which is probably a compensatory increase caused by depression of the heme content. Consequently, it is suggested that sulfamerazine inhibits the synthesis of heme at the Uroporphyrinogen I synthetase step to impair hemoprotein formation and cytochrome P-450-mediated hepatic drug metabolism.