Characterization of selective induction and alteration of xenobiotic biotransforming enzymes by vanadium during diethylnitrosamine-induced chemical rat liver carcinogenesis
A. Bishayee et al., Characterization of selective induction and alteration of xenobiotic biotransforming enzymes by vanadium during diethylnitrosamine-induced chemical rat liver carcinogenesis, ONCOL RES, 11(1), 1999, pp. 41-53
Our recent studies have shown that vanadium, a dietary micronutrient, has a
n inhibitory response against experimentally induced rat liver carcinogenes
is. In the present study, the effect of vanadium on hepatic xenobiotic biot
ransformation in rats exposed to diethylnitrosamine (DENA, 200 mg/kg, IF) w
as investigated to elucidate a possible mechanism of vanadium-mediated prev
ention of chemical carcinogenesis. Supplementary vanadium in drinking water
at 0.5 parts per million (ppm) was employed ad lib before and after the in
tiation with DENA, before the initiation only, or during the promotional ev
ent. After 20 weeks, there was a significant reduction of hepatocyte nodule
s (HNs) (P < 0.01), nodule multiplicity (P < 0.001), and the number of nodu
les more than 3 mm in size in the long-term vanadium-supplemented rats than
their DENA control counterparts. Total cytochrome P450 and b(5) contents a
s well as cytochrome P350 2E1 (CYP2E1, EC 1.5.99), aryl hydrocarbon hydroxy
lase (AHH, EC 1.14.14.2), and UDP-glucuronyl transferase (UDPGT, EC 2.4.1.1
7) activities in the microsomal fractions of HNs and nonnodular surrounding
parenchyma (NNSP) were found to be significantly decreased in DENA control
group compared to untreated normal control. Though supplementary vanadium
had little or no influence on the contents of cytochrome P350 and b(5) and
activities of CYP2E1 and AHH in HNs and NNSP, it substantially elevated the
UDPGT activity in both HNs and NNSP liver areas. DENA treatment alone also
brought about a sharp decrease in cytosolic UDP-glucose dehydrogenase (EC
1.1.1.22), DT-diaphorase (EC 1.6.99.2), and glutathione S-transferase (EC 2
.5.1.18) activities in HNs and NNSP compared to normal liver. Supplementary
vanadium was found to exert a marked induction in these cytosolic enzymes
in HNs as well as NNSP when compared to DENA control. A positive correlatio
n of phase I and phase II drug metabolizing enzymes in HNs or NNSP was alwa
ys observed in DENA or DENA plus long-term vanadium-treated group. It is co
ncluded that the chemoprotective effect of vanadium may be attributed to th
e substantial elevation of phase II conjugating enzymes, which may lead to
a move and shift of the metabolic profile that may reduce the intracellular
concentration of carcinogen-derived reactive intermediates.