The
catecholamine epinephrine is known to repress expression of hepatic drug metabolizing
enzymes such as
cytochromes P-450. The present study was designed to determine whether
epinephrine may also target expression of main hepatic drug transporters, that play a major role in liver detoxification and are commonly coordinately regulated with drug detoxifying
enzymes. Treatment of primary human hepatocytes with 10μM
epinephrine for 24h repressed
mRNA expression of various transporters, such as the sinusoidal influx transporters NTCP, OATP1B1, OATP2B1, OAT2, OAT7 and OCT1 and the efflux transporters MRP2, MRP3 and BSEP, whereas it induced that of MDR1, but failed to alter that of BCRP. Most of these changes in transporter
mRNA levels were also found in
epinephrine-exposed human highly-differentiated
hepatoma HepaRG cells, which additionally exhibited reduced
protein expression of OATP2B1 and MRP3, increased expression of
P-glycoprotein and decreased transport activity of NTCP, OATPs and OCT1.
Epinephrine effects towards transporter
mRNA expression in human hepatocytes were next shown to be correlated to those of the selective β2-adrenoreceptor (ADR) agonist
fenoterol, of the
adenylate cyclase activator
forskolin and of the cAMP analogue
8-bromo-cAMP. In addition, the non-selective β-ADR antagonist
carazolol and the selective β2-ADR antagonist ICI-118,551, unlike the α-ADR antagonist
phentolamine, suppressed
epinephrine-mediated repressions of transporter
mRNA expression. Taken together, these data indicate that
epinephrine regulates in vitro expression of main hepatic drug transporters in a β2-ADR/
adenylate cyclase/cAMP-dependent manner. Hepatic drug transport appears therefore as a target of the β2-adrenergic system, which may have to deserve attention for drugs interacting with β2-ADRs.