Inhibition of mixed-function oxidase activities in vitro and in vivo: comparisons between kidney and liver

The concentration-dependent abilities of SKF 525-A, metyrapone (MET), piperonyl butoxide (PB), allyl-isopropylacetamide (AIA) and alpha-naphthoflavone (7,8-benzoflavone; ANF) to inhibit the activities of p-chloro-N-methylaniline-N-demethylase (PCNMA) and aryl hydrocarbon hydroxylase (AHH) in vitro were determined in microsomal and postmitochondrial supernatant (PMS) fractions of homogenates prepared from kidneys and livers of rats and mice. Renal microsomal AHH was less sensitive to modulation by SKF 525-A, MET and ANF in vitro than was hepatic microsomal AHH, but renal and hepatic microsomal AHH were equisensitive to inhibition by PB. AIA did not inhibit AHH activities in vitro. Renal AHH and PCNMA activities in PMS fractions were less sensitive to inhibition by SKF 525-A, MET and PB than were hepatic AHH and PCNMA activities. The temporal characteristics of enzyme inhibition in vivo were studied in kidneys and livers removed 1, 2, 4 or 12 h after treatment of the animals with 75 mg kg-1 SKF 525-A or 600 mg kg-1 PB. The degree of inhibition of AHH and PCNMA activities produced by i.p. administration of the inhibitors were greater quantitatively in liver PMS than in kidney PMS, and the degree of inhibition of PCNMA activity in both organs was much less than that of AHH activity. The differences in sensitivity of renal and hepatic AHH and PCNMA activities to the inhibitors may have been due to organ-specific differences in the affinities of the inhibitors for interaction with the active site(s) on cytochrome P-450.