Inhibition of human adult and fetal heme oxygenase by new synthetic heme analogues.
Heme oxygenase (HO) is the rate-limiting enzyme for heme degradation, and elevated levels of HO may be associated with a variety of pathologic disturbances. A limited number of HO inhibitors such as the metalloporphyrins have been proposed as possible chemotherapeutic agents for the treatment of hyperbilirubinemia. We undertook the study of various natural newly synthesized heme analogues as possible inhibitors of HO in human adult and fetal liver microsomes. We investigated two compounds with substitutions at the 2 and 4 position of the porphyrin ring, iron deuteroporphyrin 2,4 disulfonic (1a) and iron deuteroporphyrin 2,4 bis glycol (1b), and two compounds with substitutions of aromatic groups on the methene bridges of the porphyrin molecule, meso-tetra-4-carboxyphenyl-porphine (2a) and meso-tetra-4-sulfonatophenyl-porphine (2b). When these heme analogues were incubated in the reaction media in the presence of heme, two of the analogues (1a) and (1b) inhibited the conversion of heme to bilirubin. This inhibition was 97% and 65% respectively for (1a) and (1b) when both were present in 30 microM concentrations. Both of these compounds exhibited competitive type inhibition. The kI for the more potent inhibitor, (1b), was determined to be 0.30 microM. Porphyrins with aromatic substitutions at the methene bridges (2a, 2b) did not inhibit the conversion of heme to bilirubin, even at relatively high concentrations. Furthermore, the specific activity of HO was significantly greater (5X) in fetal microsomes as contrasted with adult microsomes as contrasted with adult microsomes. Even though fetal microsomes had greater HO activity, 5 microM of compound (1b) caused a similar degree of inhibition in both adult and fetal preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
Mitrione
S M
SM
Department of Medicine, New York Medical College, Valhalla 10595.
Villalon
P
P
Lutton
J D
JD
Levere
R D
RD
Abraham
N G
NG
D000328:Adult; D003905:Deuteroporphyrins / Q000494:pharmacology*; D005333:Fetus / Q000201:enzymology; D006418:Heme / Q000031:analogs & derivatives* / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D006801:Humans; D006932:Hyperbilirubinemia / Q000188:drug therapy; D066298:In Vitro Techniques; D008665:Metalloporphyrins; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D011166:Porphyrins / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology
D003905:Deuteroporphyrins; D008665:Metalloporphyrins; D011166:Porphyrins; D011524:Protoporphyrins; C057391:iron deuteroporphyrin 2,4-bis(glycol); D006418:Heme; C032628:tin protoporphyrin IX; D006899:Mixed Function Oxygenases; D006419:Heme Oxygenase (Decyclizing)