Science Inventory

A COMPARISON OF THE METABOLISM OF METHOXYRESORUFIN, ACETANILIDE AND CAFFIENE IN RAT AND HUMAN CYP1A2 SUPERSOMES AND THEIR INHIBITION BY 2, 3, 7, 8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)

Citation:

Staskal, D., D. G. Ross, L. Birnbaum, AND M J. DeVito. A COMPARISON OF THE METABOLISM OF METHOXYRESORUFIN, ACETANILIDE AND CAFFIENE IN RAT AND HUMAN CYP1A2 SUPERSOMES AND THEIR INHIBITION BY 2, 3, 7, 8-TETRACHLORODIBENZO-P-DIOXIN (TCDD). Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, Utah, March 9-13, 2003.

Description:

A COMPARISON OF THE METABOLISM OF METHOXYRESORUFIN, ACETANILIDE AND CAFFIENE IN RAT AND HUMAN CYP1A2 SUPERSOMES AND THEIR INHIBITION BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD). DF Staskal1, DG Ross2, LS Birnbaum2 and MJ DeVito2 1Curriculum In Toxicology, UNC-CH, Chapel Hill NC, USA; 2ETD, NHEERL, ORD, US EPA, RTP, NC, 27711, USA.
CYP1A2 is highly expressed in both rats and humans. TCDD and related chemicals induce and bind to these proteins. The binding of TCDD and related chemicals to CYP1A2 leads to their sequestration in hepatic tissue. The present study compares the metabolism of prototype CYP1A2 substrates in rat and human CYP1A2 + P450reductase SUPERSOMES (GenTest Corporation, Woburn, MA) and the ability of TCDD to inhibit these reactions. For the O-demethylation of methoxyresorufin, the Km was similar between human and rat CYP1A2, 0.10 and 0.09 nM respectively. Rat supersomes had a slightly higher Vmax than human supersomes, 3.5 and 2.4 pmol/min/mg CYP1A2. TCDD inhibited methoxyresorufin metabolism with Ki values of 0.3 and 0.06 uM in the human and rat supersomes respectively. Caffeine was metabolized by both human and rat CYP1A2 supersomes. The estimated Vmax was higher in the human compared to the rat supersomes, 5.0 and 2.2 nmol/min/mg CYP1A2, respectively. The Km was also higher in the human (6.5 mM) compared to the rat (0.9 mM) supersomes. The metabolism of acetanilide to 4-hydroxy acetanilide was similar in the human and rat supersomes. The Vmax was 2.8 and 5.9 nmol/min/mg protein, in human and rat supersomes, respectively. The Km was 19.1 mM in human supersomes and 74.5 mM in rat supersomes. Initial studies indicate that TCDD inhibits both caffeine and acetanilide metabolism in rat and human supersomes. These data demonstrate that the in vitro metabolism of prototype substrates is similar between the rat and human CYP1A2 supersome preparations and that TCDD inhibits the metabolism of these substrates by both rat and human CYP1A2. Because of the potential for inhibition of CYP1A2 activity by TCDD, studies examining CYP1A2 induction in TCDD exposed populations using these substrates should be viewed cautiously. (This work was supported in part by NIEHS grant # T32 ES07126 (DS). This abstract does not reflect EPA policy.)

Record Details:

Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Product Published Date: 03/09/2003
Record Last Revised: 12/22/2005
Record ID: 115976

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY

EXPERIMENTAL TOXICOLOGY DIVISION

PHARMACOKINETICS BRANCH