reductase (NADPH-cytochrome P-450 reductase) and one
of at least six molecular species of cytochrome P-450. The
overall reaction is initiated by combining the substrate
(XH) with the ferric form of P-450 to produce the ferrous
form by accepting electrons from NADPH-cytochrome
P-450 reductase (steps a and b, Figure 14-24). The re-
ductase contains one molecule each of FMN and FAD.
The reduced P-450-substrate complex binds molecular
oxygen, which becomes activated upon acceptance of an
electron from the heme iron (steps c and d). The P-450-
substrate-oxygen complex accepts a second electron from
either NADPH-cytochrome-P-450 reductase (step e) or
(step f). In the final steps (g-j), one oxy-
gen atom receives two protons to form a water molecule,
and the other oxygen forms the hydroxyl group of the sub-
strate. The regenerated ferric form of P-450 initiates'the
next cycle. Supply of the second electron pair is via the
electron transport system, which is a mi-
nor pathway used principally for the desaturation of fatty
acids. Cytochrome b5, a microsomal membrane-heme pro-
tein, receives electrons from NADH via the flavoprotein
NADH-cytochrome bs reductase. Superoxide anion can
also be formed as a byproduct in the cytochrome P-450
The hepatic cytochrome P-450 system exhibits a broad
substrate specificity, and many lipophilic compounds in-
cluding drugs, chemicals, and endogenous metabolites are
oxidized by it (Table 14-8). The hydroxylated compounds
are converted to more polar metabolites by conjugation
with glucuronate, sulfate, amino acids, or acetate that is
catalyzed by appropriate transferases. The polar metabo-
lites are excreted by either the biliary-intestinal or the renal
Occasionally, the cytochrome P-450 system converts
some chemicals to reactive species with carcinogenic
potential (e.g., polycyclic hydrocarbons). The hepatic mi-
crosomal cytochrome P-450 system is inducible by many
of its substrates. The cytochrome P-450 of adrenal cortical
mitochondria is involved in steroid hydroxylase reactions,
and this system contains iron-sulfur (Fe
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Electron Transport and Oxidative Phosphorylation