Metabolism of Benzene in Nonfasted, Fasted, and Aryl-Hydroxylase. Inhibited Rats

Metabolism of Benzene in Nonfasted, Fasted, and Aryl-Hydroxylase. Inhibited Rats

5 Pages · 2003 · 331 KB · English

glucuronide excretion (P < O.OOl), but fasted animals injected with benzene exhibit an increase in glucuronide excretion which is approximately three times the increase noted in nonfasted benzene-injected rats. The administration of P-DDH inhibits the excretion of benzene as the glucuronide (Fig. 1

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TOXICOLOGY AND APPLIED PHARMACOLOGY 7, 767771 (1965) Metabolism of Benzene in Nonfasted, Fasted, and ArylHydroxylase Inhibited Rats’ HERBERT H CORNISH AND RICHARD C &~AN Department of Industrial Health, School of Public Health, Institute of Industrial Health, University of Michigan, Ann Arbor, Michigan 48104 Received June 26, 1964 The metabolism of benzene has been intensively studied, and its metabolic fate in the rabbit is well documented (Williams, 1959) Although partially excreted in the expired air, 304076 of ingested or inhaled benzene is hydroxylated and excreted as various phenolic products These may appear in the urine in free or conjugated form Recent studies of the enzymatic hydroxylating mechanism in liver indicate that this enzyme system is present in the microsomal fraction of liver cells (Mitoma et al, 1956) and requires TPNH and oxygen for activity It appears that the hydroxylating enzyme system is also responsible for a number of other metabolic processes, including Ndemethylation A report by Roth and Bukovsky (1961) indicates that the Nde methylating enzyme activity of rabbit liver drops almost to zero after 24 hours of fasting If hydroxylating activity is also depressed to this extent by fasting, then the immediate nutritional state of animals during toxicity testing procedures may play a most important role in determining the degree of toxicity which becomes apparent during the test period One can foresee that aromatic compounds which are hydroxylated to produce metabolites more toxic than the parent compound would have an apparent decreased toxicity in animals unable to hydroxylate the ingested compound Conversely, compounds hydroxylated to yield metabolites which are less toxic than the parent compound would appear more toxic in animals with impaired hydroxylating mechanisms Thus fasting, or the presence of chemical compounds that inhibit hydroxylation, may alter the apparent toxicity of ingested chemicals pDiethyl aminoethyldiphenylpropylacetate hydrochloride” (PDDH) is a compound which has been shown to inhibit the hydroxylating enzyme system (Cook et al, 1954) The present study was designed to determine the effect of fasting and the injection of PDDH on the acute oral toxicity and metabolic fate of benzene METHODS Acute oral toxicity Male SpragueDawley rats of the Holtzman strain, weighing 200250 g, were utilized in the acute toxicity tests Oral toxicity was determined by feeding geometrically graded dosages of reagentgrade benzene3 to groups of 10 rats at each dosage The LDsO and 957% confidence level were calculated by the method 1 This study was supported, in part, by US Public Health Service research grant no MH 03692 from the Institute of Mental Health, National Institutes of Health 2 SKF 525A, Smith, Kline & French Laboratories, Philadelphia, Pennsylvania 3 Mallinckrodt Chemical Works, St Louis, Missouri 767 768 HERBERT H CORNISH AND RICHARD C RYAN of Weil (1952) The LD:,,,‘s of benzene were determined for rats on the following treatments: (a) nonfasted; (b) fasted for 24 hours; (c) nonfasted, but injected with 80 mg/kg of /3DDH intraperitoneally 45 minutes prior to oral administration of benzene; and (d) fasted for 24 hours and injected with 80 mg/kg of PDDH 45 minutes prior to oral administration of benzene Metabolism Male rats similar to those used in the acute toxicity tests, weighing 200250 g, were maintained on a normal test diet4 and in individual metabolism cages designed for the collection of urine uncontaminated by food or feces Complete urine samples were collected by a gentle squeezing of each animal at the end of the ,Xhour period The samples were diluted to 20 ml with water, mixed, filtered, and utilized for the determination of phenols and glucuronides The Dische (1947) method was used for the determination of glucuronides Standard solutions were prepared from recrystallized nglucuronic

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