target enzyme is the substrate that in the process of catalytic turnover is
metabolized to a reactive intermediate that inactivates the enzyme irreversibly
(suicide inhibition). The latter is MI complexation in which CYP produces a
metabolite with the capacity to bind tightly to the CYP heme (Pessayre et al.,
1982; Mayhew et al., 2000). The distinction between CYP inactivation and MI
complexation is that, in the latter, the hemoprotein is not actually destroyed,
even though it is rendered catalytically inert. There are most three pathways for
inactivation of the enzyme by the reactive intermediate: covalent modifications
on the apoprotein and the heme, and crosslink between apoprotein and heme.
FIGURE 16.4 Competitive inhibition of sulfaphenazole in the metabolism of
diclofenac by human liver microsomes.Km(16.70.07mM),Vmax(4.10.77 nmol/
min/mg) andKi(0.28400.01mM) were generated using the equantion of competitive
inhibition in Table 16.3. (Yao et al., 2007).
IRREVERSIBLE INHIBITION 527