Drug Metab Dispos. 1998 Jan;26(1):66-72.  

Suppression of xenobiotic-metabolizing enzyme expression in rats by acriflavine,
a protein kinase C inhibitor. Effects on epoxide hydrolase, glutathione
S-transferases, and cytochromes p450.

Kim SG, Cho JY, Chung YS, Ahn ET, Lee KY, Han YB.

College of Pharmacy, Duksung Women's University, Seoul, Korea.

The effects of acriflavine (ACF), a protein kinase C inhibitor, on the
expression of hepatic microsomal epoxide hydrolase (mEH), glutathione
S-transferases (GSTs), and cytochrome P450 (P450) were assessed in rat hepatic
tissue. Northern blot analysis revealed that treatment of rats with thiazole,
allyl disulfide (ADS), oltipraz, or clotrimazole at a single dose of 100 mg/kg
resulted in 7-18-fold increases in mEH mRNA levels at 24 hr, whereas concomitant
ACF treatment (20 mg/kg, im) caused 50-95% inhibition of the chemical-induced
increases in hepatic mEH mRNA levels. rGSTA2, rGSTA3, and rGSTM1 mRNA levels
were also significantly suppressed at 24 hr in response to a single dose of ACF
(20 mg/kg, im). Animals treated with both ACF and ADS showed complete blockage
of mEH and GST gene expression as early as 12 hr after treatment. ADS-inducible
increases in mEH and rGSTA2 mRNA levels were suppressed at 24 hr after treatment
with ACF, in a dose-related manner, with 50% inhibitory dose (ID50) values of
2.0-2.3 mg/kg, whereas glyceraldehyde-3-phosphate dehydrogenase mRNA levels were
not altered. Immunoblot analysis revealed that ACF (15 mg/kg/day, im, for 3
days) inhibited induction of mEH or rGSTA2 protein by ADS (100 mg/kg/day, po,
for 3 days). The levels of hepatic P450 2B1/2, P450 2C11, and P450 3A1/2 were
decreased in rats treated with ACF (15 mg/kg/day, im, for 3 days), whereas P450
1A2 and P450 2E1 expression was not affected. Treatment of rats with ACF in
combination with gadolinium chloride, which inhibits mEH and GST expression
through calcium channel blocking, shifted the dose-inhibitory response curves
for ACF to the left, with 7-15-fold decreases in