Cell biology of cytochrome P-450 in the liver

Abstract

Cytochromes P-450 (P-450) are members of a multigene superfamily of hemoproteins consisting the microsomal monooxygenase system with NADPH P-450 reductase (reductase) and/or reducing equivalents. Expression of many P-450 isoforms in hepatocytes is shown to be regulated at the level of transcription through interaction between cis-acting elements in the genes and DNA-binding (transacting) factors. Some isoforms of the CYP1A, 2B, 2E, and 3A subfamilies are regulated at the posttranscriptional level. For the topology of P-450 and reductase molecules in ER membrane of hepatocytes, models from stopped flow analysis and electron spin resonance are proposed. The densities of total P-450 and reductase molecules are revealed to be high enough to support the cluster model, suggesting that about ten P-450 molecules form an aggregate and surround one reductase molecule, and therefore the two enzymes form large micelles. ER proliferation after PB administration, which had been correlated with increase in P-450 level, is shown to be probably independent of the increase in P-450 level. There are considerable discrepancies among results reported on sublobular expression of various P-450 isoforms. Causes of the discrepancies are likely to be differences in experimental conditions of histochemical detection carried out and/or in species, strain, and/or sex.