Renal reabsorption and excretion for Riboflavin

In the kidney, riboflavin that has been fi ltered through
the glomerulus can undergo either reabsorption or
secretion in the proximal tubule before it is fi nally
excreted in the urine. Reabsorption is the process
by which ribofl avin in the tubular lumen enters the
epithelial cell via the brush-border membrane, exits
the cell at the basolateral membrane and diffuses into
the peritubular capillary. Secretion is the process by
which ribofl avin in the peritubular capillary is transported
across the epithelial cell and into the tubular lumen in the opposite direction to reabsorption. As
at least 40% of plasma ribofl avin is thought to be unbound
in humans (Rose, 1988), renal reabsorption is
an important conservation mechanism. Renal secretion
removes excess ribofl avin from the body at a rate
several times higher than the glomerular fi ltration
rate. The kidney, together with the intestine, therefore
plays an important role in maintaining ribofl avin
homeostasis in the body.

Kumar et al. (1998) studied riboflavin uptake by
cultures of human-derived renal proximal tubule
epithelial cells. They demonstrated uptake via an energy-
dependent, Na+-independent, carrier-mediated
system that adapted according to the concentration of
ribofl avin in the growth medium. The adaptive regulatory
effect of ribofl avin was mediated via changes
in the number and/or activity as well as affi nity of the
ribofl avin uptake carriers. Using specifi c modulators
of intracellular signal transduction pathways, it was
shown that protein kinase A, protein kinase C and
protein tyrosine kinase were not involved in regulating
ribofl avin uptake. In contrast, inhibition of the
Ca2+/calmodulin signal transduction pathway resulted
in a signifi cant inhibition of ribofl avin uptake,
implicating this system in the regulation of ribofl avin
transport. The effect of one inhibitor, calmidazolium,
appeared to be mediated through decreases in both
the number/activity and affi nity of the ribofl avin
uptake carriers.

Yanagawa et al. (2000) studied riboflavin transport
in rabbit renal proximal tubules by using the in vitro
isolated perfused tubule. This technique is ideal for
studying bi-directional tubular transport processes
because it allows unidirectional fl uxes to be measured
separately in a defi ned tubular segment. Both reabsorption
and secretion were found to be infl uenced by
ribofl avin concentration. At 0.1 μM ribofl avin concentration,
secretion was higher than reabsorption so
that net ribofl avin transport occurred in the direction
of secretion. Lowering the ribofl avin concentration
to 0.01 μM reduced both reabsorption and secretion,
but the two fl uxes were not signifi cantly different and
so no net ribofl avin transport occurred. In contrast,
both reabsorption and secretion were increased when
the ribofl avin concentration was raised to 1 μM, leading
to a signifi cantly greater net ribofl avin secretion.
Both fl uxes were abolished by the metabolic inhibitor
iodoacetate and signifi cantly lowered by lumichrome,
indicating dependence on energy and a carrier, respectively.
Secretion, but not reabsorption, was inhibited
by the anion inhibitor probenecid and paraaminohippuric
acid (an organic anion), indicating
that the organic anion transport system is involved in
tubular ribofl avin secretion. Changes in luminal pH
over the physiological range (7.0–8.0) did not affect
reabsorption, but secretion was inhibited when the
bath pH was increased to 8.0. Secretion was inhibited
by trifl uoperazine, indicating that the intracellular
Ca2+/calmodulin-dependent pathway may play an
important role in mediating the regulation of tubular
transport through its effect on ribofl avin secretion.
For normal adults eating varied diets, ribofl avin
accounts for 60–70% of fl avin compounds in the
urine; the remainder are riboflavin metabolites (Mc-
Cormick, 1994). Urinary excretion studies carried
out in humans have suggested that any ribofl avin
secreted into the bile is almost fully reabsorbed, i.e.
the vitamin is subject to enterohepatic cycling (Jusko
& Levy, 1967).