Studies on the inhibition of human cytochromes P450 by selenocysteine Se-conjugates.
1. To investigate whether cytochrome P450 (P450) inhibition can contribute to the chemopreventive activity of selenocysteine Se-conjugates (SeCys conjugates), 21 SeCys conjugates were screened for their inhibitory potency towards seven of the most important human P450s. 2. The majority of the SeCys conjugates produced near complete inhibition of CYP1A1 at a concentration of 250 microm. The most potent inhibitor, Se-benzyl-L-selenocysteine, displayed an IC50 of 12.8 +/- 1.2 microm. CYP2C9, -2C19 and -2D6 were moderately (50-60%) inhibited by the SeCys conjugates. CYP1A2, -2E1 and -3A4 were least inhibited. 3. Studies on the susceptibility of CYP1A1 to SeCys conjugates implicated a thiol-reactive intermediate, as evidenced by reduced inhibition levels in the presence of glutathione and N-acetyl cysteine. Uncoupling of the P450-catalytic cycle was of no importance as ROS scavengers did not influence inhibition levels. 4. P450 inhibition by two physiologically relevant metabolite classes of SeCys conjugates was also studied. N-acetylation of SeCys conjugates consistently increased the inhibitory potency towards CYP1A2, -2C19, -2E1 and -3A4. Beta-lyase catalysed bioactivation of alkyl-substituted SeCys conjugates or Se-benzyl-L-selenocysteine produced little or no additional inhibition of P450 activity. For Se-phenyl-L-selenocysteine, however, significant increases in P450 inhibition were obtained by beta-lyase pre-incubation. 5. It is concluded that the potent and relatively selective CYP1A1 inhibition exerted by SeCys conjugates may contribute to their chemopreventive activity.
Venhorst
J
J
Leiden/Amsterdam Center for Drug Research, Division of Molecular Toxicology, Department of Pharmacochemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Rooseboom
M
M
Vermeulen
N P E
NP
Commandeur
J N M
JN
D000107:Acetylation; D001667:Binding, Competitive; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005456:Fluorescent Dyes; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D012643:Selenium / Q000378:metabolism*; D017279:Selenocysteine / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D005456:Fluorescent Dyes; D007527:Isoenzymes; D017279:Selenocysteine; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1; D012643:Selenium