Cytochrome P-450 isozyme selectivity in the oxidation of acetaminophen

Abstract

Highly purified isozymes of cytochrome P-450 catalyzed the formation of 3-glutathion-S-ylacetaminophen (GS-APAP) and 3-hydroxyacetaminophen (3-OH-APAP) from acetaminophen (APAP). A major isozyme from untreated male rats (P-450UT-A) catalyzed the formation of ca. 2.0 nmol/nmol of P-450/10 min of 3-OH-APAP and approximately 7.2 nmol of GS-APAP/nmol of P-450/10 min. Antibodies specific for cytochrome P-450UT-A caused a decrease in the amounts of both metabolites produced in microsomal incubations. In contrast to these results, two other constitutive P-450 isozymes from rat liver, cytochrome P-450UT-F and the female specific isozyme P-450UT-I, produced less of both oxidative metabolites. Moreover, they produced significantly more of the catechol metabolite than the glutathione conjugate. These results are in accord with the observation that male rats are more susceptible to acetaminophen hepatotoxicity than female rats. Isozymes induced by phenobarbital also produced more of the catechol than the glutathione conjugate. Conversely, the major isozyme induced by beta-naphthoflavone, cytochrome P-450 beta NF-B, produced a significantly greater amount of GS-APAP than 3-OH-APAP. When comparison was made to a major phenobarbital inducible form (cytochrome P-450PB-B) a definite isozyme specificity for the formation of the two metabolites was seen. The catechol was formed at rates of 2.21 and 0.53 nmol/nmol of P-450/10 min by cytochromes P-450PB-B and P-450 beta NF-B, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of Novel Toxicity-associated Metabolites by Metabolomics and Mass Isotopomer Analysis of Acetaminophen Metabolism in Wild-type and Cyp2e1-null Mice

“…The immediate precursor of 3-CH 3 O-APAP is 3-hydroxyacetaminophen (3-OH-APAP), the catechol metabolite of APAP. It has been shown that the reaction mechanism of 3-OH-APAP formation is different from the mechanism of NAPQI (49), and CYP2E1 might not be the most efficient P450 for the generation of 3-OH-APAP in vivo (50). Although 3-OH-APAP is much less toxic than APAP, 3-CH 3 O-APAP is as toxic as APAP in vivo (48).…”

Identification of the Hepatic Protein Targets of Reactive Metabolites of Acetaminophen in Vivoin Mice Using Two-dimensional Gel Electrophoresis and Mass Spectrometry

“…icity (2)(3)(4)(5)(6)(7). At therapeutic doses, this metabolite is efficiently detoxified by reduced glutathione (GSH) to form an acetaminophen-glutathione conjugate (8).…”

Acarbose Alone or in Combination With Ethanol Potentiates the Hepatotoxicity of Carbon Tetrachloride and Acetaminophen in Rats

“…CYP1A2 is reported to be involved in the metabolic activation of AP. [42][43][44] It is certain that a large amount of ethanol given to rats as a liquid formula (DeCarli-Lieber diet 45,46 ) induces CYP1A2, as demonstrated in our own study. 47 However, in a preliminary study in which ethanol was given in drinking water (10% vol/vol), no difference was observed in the activity of CYP1A2 (oxidation of 7-ethoxyresorufin) in the ethanol-treated and nontreated rats (Tsukada et al, 1998, unpublished data).…”