Characterization of 1‐Hydroxypyrene as a Novel Marker Substrate of 3‐Methylcholanthrene‐Inducible Phenol UDP‐Glucuronosyltransferase(s)

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Abstract
Rats were treated with acetone, pyrazole, phenobarbital, 4,4′‐methylenebis‐(2‐chloroaniline) (MOCA), 3‐methylcholanthrene, creosote oil, or a mixture of polychlorinated biphenyls (Aroclor 1254) to study the inducibility and enzyme kinetics of UDP‐glucuronosyltransferases towards 1‐hydroxypyrene, which is a human metabolite and a urinary biomarker of exposure to pyrene. The rate of 1‐hydroxypyrene glucuronidation was analysed in rat liver microsomes by a fluorometric HPLC assay of the formed glucuronide. The apparent Kmand Vmaxvalues in untreated controls (Km= 0.27 mM; Vmax= 31 nmol/min./mg protein) did not differ markedly from those in rats treated with acetone, pyrazole or phenobarbital, whereas the significantly decreased Kmand increased Vmaxvalues of the rats treated with the carcinogenic chemicals, MOCA (0.11; 51), creosote (0.06; 137), 3‐methylcholanthrene (0.07; 141) or the Aroclor‐1254 polychlorinated biphenyl (PCB) mixture (0.08; 226), implicated major changes in the hepatic expression of UDP‐glucuronosyltransferases. 1‐Hydroxypyrene proved to be a high affinity substrate and a sensitive marker of the polycyclic aromatic hydrocarbon (PAH) metabolizing UDP‐glucuronosyltransferase(s). Catalytically, the most efficient isoforms were induced in creosote, 3‐methylcholanthrene and PCB‐treated rats showing Vmax/Kmratios which were 22–27 times greater than in untreated controls. Our findings suggest the existence of a 3‐methylcholanthrene type inducible and a functionally efficient low‐Km/high‐Vmaxform(s) of UDP‐glucuronosyltransferase(s) that detoxify 1‐hydroxypyrene and probably other polycyclic aromatic hydrocarbons as well.

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