RT Journal Article
SR Electronic
T1 Human cytochrome P450 isoform specificity in the regioselective metabolism of toluene and o-, m- and p-xylene.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 101
OP 108
VO 276
IS 1
A1 W Tassaneeyakul
A1 D J Birkett
A1 J W Edwards
A1 M E Veronese
A1 W Tassaneeyakul
A1 R H Tukey
A1 J O Miners
YR 1996
UL http://jpet.aspetjournals.org/content/276/1/101.abstract
AB The conversion of toluene and o-, m- and p-xylene to their respective side-chain and ring monohydroxylated metabolites by human liver microsomes was investigated. Methyl hydroxylation, to form a benzylalcohol, was the major metabolic pathway for all four methylbenzenes. With the exception of 2,4-dimethylphenol formation from m-xylene, ring hydroxylation accounted for < 5% of total metabolite formation. However, regioselectivity of ring hydroxylation was apparent, with hydroxylation occurring only at positions ortho and/or para to a methyl substituent. Toluene and each xylene isomer exhibited biphasic methylhydroxylation kinetics in human liver microsomes. The high-affinity component of each methylhydroxylation was selectively inhibited by diethyldithiocarbamate and correlated significantly with cytochrome P-4502E1 (CYP2E1) content and activities in a panel of human liver microsomes. cDNA-expressed CYP2E1 was shown to catalyze the formation of each benzylalcohol, with apparent Km values similar to those of the high affinity microsomal reactions. In contrast, the conversion of m-xylene to 2,4-dimethylphenol followed single enzyme Michaelis-Menten kinetics, was inhibited selectively by furafylline, and correlated significantly with known CYP1A2 catalyzed reactions. cDNA-expressed CYP1A2 converted m-xylene to 2,4-dimethylphenol, with an apparent Km similar to that of the microsomal reaction. Although CYP1A2 appears to be responsible for the formation of the minor (phenolic) metabolites of toluene and the xylene isomers, CYP2E1 catalyzed methylhydroxylation will be the major determinant of the clearance of these compounds in humans.