Selectivity of polycyclic inhibitors for human cytochrome P450s 1A1, 1A2, and 1B1

Chem Res Toxicol. 1998 Sep;11(9):1048-56. doi: 10.1021/tx980090+.


Human cytochrome P450s 1A1, 1A2, and 1B1 are known to have overlapping substrate specificities. All are regulated in part by the Ah locus; P450 1A2 is expressed essentially only in liver, but P450s 1A1 and 1B1 are both expressed in many extrahepatic tissues. Twenty-five polycyclic hydrocarbons, many containing acetylenic side chains, were examined as inhibitors of the three enzymes using 7-ethoxyresorufin O-deethylation as the enzyme assay in all cases. Several compounds were inhibitory at low nanomolar concentrations. 1-(1-Propynyl)pyrene and 2-(1-propynyl)phenanthrene nearly completely inhibited P450 1A1 at concentrations at which no P450 1B1 inhibition was observed. 2-Ethynylpyrene and alpha-naphthoflavone (7, 8-benzoflavone) nearly completely inhibited P450 1B1 at concentrations at which no P450 1A1 inhibition was noted. All four of the above compounds also inhibited P450 1A2. Several polycyclic hydrocarbons devoid of acetylenic groups were also inhibitory with respect to all three P450s. Some of the acetylenic compounds examined showed enhanced inhibition following preincubation with the P450s in the presence of cofactors NADPH and O2. However, of seven compounds (five acetylenes) tested with P450 1B1, only two [2-ethynylpyrene and 4-(1-propynyl)biphenyl] showed such evidence for mechanism-based inactivation. We conclude that (i) several polycyclic hydrocarbons and their oxidation products are very inhibitory with respect to human P450s 1A1, 1A2, and 1B1; (ii) of these inhibitors only some are mechanism-based inactivators; and (iii) some of the inhibitors are potentially useful for distinguishing between human P450s 1A1 and 1B1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Biotransformation
  • Cytochrome P-450 CYP1A1 / antagonists & inhibitors
  • Cytochrome P-450 CYP1A1 / metabolism
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / metabolism
  • Polycyclic Aromatic Hydrocarbons / pharmacokinetics
  • Polycyclic Aromatic Hydrocarbons / pharmacology*
  • Substrate Specificity


  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Isoenzymes
  • Polycyclic Aromatic Hydrocarbons
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP1A1