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A micropatterned human hepatocyte co-culture model allows determination of toxicity at more relevant concentrations than hepatocyte sandwich cultures

Use of human hepatocytes in sandwich cultures for determining toxicity potential is
limited by the short functional lifespan of hepatocytes (~5 days). HepatoPac is a
system of micropatterned human hepatocytes co-cultured with mouse embryonic 3T3-
J2 fibroblasts enabling functional survival of hepatocytes for >30 days. This study
was performed to determine if HepatoPac would allow for use of lower, more relevant
concentrations in toxicity studies than used with sandwich cultures. Hepatocytes
from 2 human donors were cultured in the HepatoPac system for up to 3 weeks or in
sandwich cultures for 4 days and exposed to multiples of the human Cmax of
pravastatin (PS), simvastatin (SS) or cerivastatin (CS). ATP levels, albumin secretion
and urea synthesis were used to determine the viability and function of hepatocytes at
various time points. Donor 1 results: In HepatoPac a slight decrease in ATP was seen
with CS at 50x Cmax on day 3. Concentration-related decreases in ATP, albumin
secretion and urea synthesis were seen with CS on days 7 and 15, beginning at 25x
Cmax. No significant changes were observed with PS, and with SS only albumin
secretion was affected at 50x Cmax on day 15. In sandwich cultures the only change
observed was decreased albumin with PS and CS at 50x Cmax. Donor 2 results: In
HepatoPac, concentration-related ATP depletion and decreased urea synthesis were
seen with CS on days 8 and 15 from 10x Cmax, while albumin secretion was affected
at ≥25x Cmax. The changes seen with Donor 2 were of a smaller magnitude than for
Donor 1. Only urea was affected on day 15 with SS, and no changes were seen with
PS. With sandwich cultures, very slight (<10%) decreases in ATP were seen at ≥50x
Cmax for PS and at ≥10x Cmax for CS, with no changes in albumin or urea. Overall,
the results show that extended functional life of hepatocytes may allow for
determination of toxicity at more therapeutically-relevant concentrations than
possible wi th sandwich cul tures, and that there is donor var iabi l i ty.