ALAS1 and cholestasis: PPIX, an intermediate in the heme biosynthesis pathway, is known to be a hepatotoxin, and has been implicated in cholestasis in both mice and humans.84, 85, 86 INH causes PPIX accumulation in the liver through the induction of delta-aminolevulinate synthase 1 (ALAS1) and downregulation of ferrochelatase (FECH), both of which are pivotal enzymes in regulating heme biosynthesis.83