Non-specific inhibition of cytochrome P450 activities by chlorophyllin in human and rat liver microsomes.
Chlorophyllin, a copper/sodium salt of chlorophyll used in the treatment of geriatric patients, inhibits the mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 3-amino-1-methyl-5H- pyrido[4,3-b]indole (Trp-P-2), aflatoxin B1 and benzo[a]pyrene (B[a]P). Recent in vitro and in vivo studies have shown that a molecular complex is formed between IQ and chlorophyllin, suggesting that this complex formation might be responsible for the antigenotoxic effect of chlorophyllin observed. Cytochrome P450 (P450) enzymes appear to be the major catalysts in the bioactivation of these carcinogens. We have investigated the in vitro effects of chlorophyllin on several P450 activities including ethoxyresorufin O-deethylation, benzyloxyresorufin O-debenzylation, coumarin 7-hydroxylation, 7-ethoxycourmarin O-deethylation, B[a]P 3-hydroxylation, and chlorzoxazone 6-hydroxylation. Chlorophyllin non-specifically inhibited all of P450 activities observed. Spectrally detectable P450 was also destroyed in microsomes and purified P450 in a reconstituted system in the presence of chlorophyllin and an NADPH-generating system. These results suggest that the antigenotoxic effect of chlorophyllin might be due to inhibition of P450 enzymes involving bioactivation of carcinogens in addition to molecular complex formation between carcinogens and chlorophyllin. Comparison of the apparent Ki for P450 inactivation with previously estimated constants for chlorophyllin-IQ complexation suggest that P450 inhibition should be the dominant mechanism of inhibition.
Yun
C H
CH
Department of Biochemistry, Pai-Chai University, Taejon, Korea.
Jeong
H G
HG
Jhoun
J W
JW
Guengerich
F P
FP
D000818:Animals; D002735:Chlorophyllides / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats
D002735:Chlorophyllides; D065607:Cytochrome P-450 Enzyme Inhibitors; C007020:chlorophyllin