Drug-induced porphyrin biosynthesis—XIII: Role of lipophilicity in determining porphyrin-inducing activity of aliphatic amides after blockade of their hydrolysis by bis-[ p-nitrophenyl]phosphate

Abstract

Hexanamide and heptanamide were the best substrates for a chick embryo liver amidase, and activity decreased with shorter or longer chain lengths. Amides branched at the 2-carbon atom were poor substrates and those branched at the 2- and 3-carbon atom were not hydrolyzed. Hydrolysis of both straight- and branched-chain amides was inhibited to varying extents by bis-[ p-nitrophenyl]phoshate (BNPP). Branched-chain amides, while poor substrates of the amidase, were hydrolyzed solely by a BNPP-sensitive enzyme, while the straight-chain amides were hydrolyzed by a BNPP-sensitive and a BNPP-resistant enzyme. The porphyrin-inducing activity of a series of aliphatic amides was studied in a chick embryo liver cell culture system in the presence and absence of BNPP. The potency of sterically hindered branched-chain aliphatic amides was found to be the same in the presence and absence of BNPP and could be correlated with lipophilicity. However, sterically unhindered aliphatic amides which were moderately potent in the absence of BNPP exhibited an increase in potency in the presence of BNPP. The potency of the straight-chain aliphatic amides after BNPP pretreatment could be correlated with lipophilicity. It was concluded that porphyrin-inducing activity of aliphatic amides in chick embryo liver cell culture depends upon lipophilicity and resistance to rapid metabolism to compounds of lower lipophilicity.