Y. Amet et al., NONINVOLVEMENT OF CYP2E1 IN THE (OMEGA-1)-HYDROXYLATION OF FATTY-ACIDS IN RAT-KIDNEY MICROSOMES, Biochemical pharmacology, 54(8), 1997, pp. 947-952
Pyrazole, acetone, and ethanol are known to induce cytochrome P450 2E1
(CYP2E1) and fatty acid (omega-1)-hydroxylation in rat liver microsom
es. However, the nature of the P450 enzyme involved in this (omega-1)
hydroxylation has not been clearly established in extrahepatic tissues
such as kidney. Four enzymatic activities (hydroxylations of chlorzox
azone, dr-nitrophenol, and two fatty acids) were assayed in kidney mic
rosomal preparations of rats treated with CYP2E1 inducers. Per os trea
tment resulted in large increases (threefold to fivefold) in the chlor
zoxazone and 4-nitrophenol hydroxylations, and up to a ninefold increa
se when ethanol was administered by inhalation. However, neither the o
mega-hydroxylation nor the (omega-1)-hydroxylation of fatty acids was
modified. Immunoinhibition specific to CYP2E1 did not significantly de
crease the omega- and (omega-1) lauric acid hydroxylations, while the
polyclonal anti-CYP4A1 antibody inhibited in part both the omega- and
(omega-1)-hydroxylations. Chemical inhibitions using either CYP2E1 com
petitive inhibitors (such as chlorzoxazone, DMSO, and ethanol) or P450
mechanism-based inhibitors (such as diethyldithiocarbamate and 17-oct
adecynoic acid) led to a partial inhibition of the hydroxylations. All
these results suggest that fatty acid (omega-1) hydroxylation, a high
ly specific probe for CYP2E1 in rat and human liver microsomes, is not
mediated by CYP2E1 in rat kidney microsomes. In contrast to liver, wh
ere two different P450 enzymes are involved in fatty acid omega- and (
omega-1)-hydroxylations, the same P450 enzyme, mainly a member of the
CYP4A family, was involved in both hydroxylations in rat renal microso
mes. (C) 1997 Elsevier Science Inc.