Elsevier

Biochemical Pharmacology

Volume 39, Issue 3, 1 February 1990, Pages 489-498
Biochemical Pharmacology

High affinity phenacetin O-deethylase is catalysed specifically by cytochrome P450d (P450IA2) in the liver of the rat

https://doi.org/10.1016/0006-2952(90)90055-PGet rights and content

Abstract

Phenacetin is metabolized primarily by O-deethylation to paracetamol (POD activity), a reaction catalysed by cytochrome P450. The high affinity component of POD activity is inducible in rat liver by treatment of the animals with polycyclic aromatic hydrocarbons. Following treatment with hydrocarbons such as 3-methylcholanthrene (MC) and isosafrole (ISF) both cytochromes P450c (P450IA1) and P450d (P450IA2) are also induced in rat liver. Studies with the reconstituted enzymes have shown that both forms of P450 catalyse phenacetin O-deethylation at rates that exceeded that of the high affinity component of activity of hepatic microsomal preparations from 3-methylcholanthrenetreated rats (at 4μM phenacetin: P450c, 440 ± 40 pmol/nmol/min; P450d, 1030 ± 10 pmol/nmol/min; microsomal fraction, 163 pmol/mg/min). Specific inhibitory antibodies (both monoclonal and monospecific polyclonal) were used to define the specificity of microsomal POD activity. These studies have shown that hepatic high affinity POD activity is exclusively catalysed by cytochrome P450d in both untreated rats and in rats pretreated with MC.

References (36)

Cited by (57)

  • Molecular cloning and functional analysis of cytochrome P450 1A2 from Japanese monkey liver: Comparison with marmoset cytochrome P450 1A2

    2005, Chemico-Biological Interactions
    Citation Excerpt :

    Fluorescence of the supernatant was measured at 580/600 nm (excitation/emission wavelength) using a Hitachi F-4500 fluorescence spectrophotometer. PN O-dethylase activity was measured by a published method [14] with modifications. Briefly, the ice-cold incubation mixture (500 μl) in a brown glass conical tube (10 ml) with a stopper contained 5 mM G-6-P, 1 IU of G-6-P dehydrogenase, 5 mM MgCl2, 0.1 mM EDTA and 100 μM PN in 100 mM potassium phosphate buffer (pH 7.4).

  • Study of P450 function using gene knockout and transgenic mice

    2003, Archives of Biochemistry and Biophysics
    Citation Excerpt :

    Phenacetin is metabolized by P450 to the widely used drug actetaminophen that itself can be converted to a toxic metabolite by P450s as described above. In vitro studies indicate that CYP1A2 metabolizes phenacetin [27]. To determine whether CYP1A2 is involved in phenacetin toxicity, the CYP1A2 null mice were examined by feeding diets containing phenacetin [28].

View all citing articles on Scopus

Present address: College of Pharmacy, Rutgers University, Busch Campus, Piscataway, NJ 08855, U.S.A.

View full text