Effects of repeated intravenous administration of haem arginate upon hepatic metabolism of foreign compounds in rats and dogs

Abstract

1 Haem arginate is a new haem compound, recently introduced for the treatment of acute hepatic porphyrias. Porphyrias are characterized biochemically by decreased formation ofhaem due to defects in certain enzyme activities involved in the haem biosynthesis. 2 Haem is essential for cell respiration and oxidative biotransformation. Hepatic drug metabolism, haem biosynthesis and catabolism were investigated after repeated intravenous administration of haem arginate in connection with toxicity studies. 3 The daily doses ofhaem for rats were 4, 12 and 40mg kg-and for dogs 3 and 9mg kg-' for 30 days and for 28 days, respectively. 4 Hepatic microsomes were used in the assay of the following drug metabolizing enzymes: cytochrome P-450 and b5, aminopyrine N-demethylase, ethoxyresorufin O-deethylase and UDPglucuronyl transferase. The assay of NADPH-cytochrome C-reductase and the enzymes reflecting synthesis and metabolism ofhaem in the liver (6-aminolaevulinic acid synthase, 6-aminolaevulinic acid dehydratase, uroporphyrinogen I-synthase, uroporphyrinogen decarboxylase, haem synthase, haem oxygenase and biliverdin reductase) were performed from 20,000g supernatants. 5The lowest dose administered to rats and dogs did not cause any significant changes compared to controls in the parameters measured. 6 The highest doses significantly increased the activities of haem oxygenase and uroporphyrinogen Isynthase but decreased concentrations or activities of other enzymes, e.g. cytochrome P-450 and ethoxyresorufin O-deethylase. 7 The results show that it is important to avoid overdosage of haem when restoration of mixed function oxygenase activity is needed.

Haem arginate improves hepatic oxidative metabolism in variegate porphyria.

“…In nonporphyric animals, haematin (4 mg kg-) impaired hepatic drug metabolism (Muller-Eberhard et al, 1983), but haem arginate during 1 month of daily intravenous doses equivalent to 3-4 mg haem kg-1 did not change the concentration of cytochrome P-450 or numerous other parameters of drug metabolism (Tokola, 1987). This difference may be due, for example, to the poor stability of haematin, causing decomposition products with toxic actions (Goetsch & Bissell, 1986).…”

Multiple roles of haem in cystathionine β-synthase activity: implications for hemin and other therapies of acute hepatic porphyria

“…The first involves CO [20] produced from the haem oxygenase reaction following induction of HO 1 by haem. Induction of HO 1 mRNA expression, protein levels and/or activity by haem arginate has been demonstrated in rats, dogs and humans [23][24][25][26][27]. The second mechanism involves PLP depletion following its consumption by kynurenine aminotransferase (KAT) and kynureninase (kynase) following activation of liver TDO by haem (see further below).…”

“…A time-course study in rats [23] showed that HO 1 induction by haem arginate is highest (~ 5-fold) at 5-7h and remains pronounced (~3-fold) at 24h after the last of 4 daily injections of 15 mg/kg body weight each, with comparable levels of induction by hemin and haem arginate. At 24h, loss of haem is apparent from the decreased levels of cytochrome P-450 and impaired metabolism of arachidonic acid [23] and several drugs [24]. Induction of HO 1 protein and activity in humans was still pronounced at 48h after intravenous administration of haem-albumin [26].…”

“…With multiple dosing of haem arginate, the plasma T 1/2 of haem rises from 11 h after the first dose to ∼18 h after the fourth dose [ 28 ]. 5-ALAS 1 activity was measured in only one study [ 24 ] in rats and dogs 24 h after a 30-day daily treatment with haem arginate. 5-ALAS 1 activity was unaltered in rats, but increased in dogs.…”