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Hexachlorophene: Its Absorption, Distribution

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Hexachlorophene: Its Absorption, Distribution AN ABSTRACT OF THE THESIS OF Allen Jay Gandolfi for the Doctor of Philosophy (Name) (Degree) in Biochemistry presented on 46, (00.271/A (Major) (Date) Title: HEXACHLOROPHENE: ITS ABSORPTION, DISTRIBUTION, EXCRETION, AND BIOTRANSFORMATION IN THE RAT AND RABBIT AND IN VITRO INTERACTION WITH RAT LIVER MICROSOMES Abstract approved: Redacted for Privacy Dr. D. R. Buhler The fate of hexachlorophene, a widely used bactericide,was investigated using both intact male rats and rabbits and livermicro- somes from male rats.Hexachlorophene administered intraperi- toneally was found to be rapidly absorbed and distributedto all the tissues of the animals.Excretion of the chemical in both species occurred slowly, with 48-83% of the dose appearing in the fecesas un- changed hexachlorophene plus a small amount of hexachloropheneglu- curonide.The rabbit and rat excreted 21-25% and 4-8% of the dose, respectively, in the urine.A glucuronide conjugate of hexachlorophene accounted for over one-half of the urinary metabolites withthe remain- der being unchanged hexachlorophene. In less than four days, about 30-45% of hexachlorophene dose was excreted in the bile as a glucuronide conjugate.Extra-biliary excretion of hexachlorophene or its metabolites was also suggested. Hexachlorophene was shown to undergo enterohepatic circulation in the rat, which would explain its long half-life in animals and its ex- cretion primarily via the feces.The glucuronide conjugate of the bisphenol excreted in the rat bile and in the rabbit urine was identified as hexachlorophene monoglucuronide. Hexachlorophene was shown not to be metabolized or conjugated in vitro by the rat liver microsomal enzyme systems. Microsomes were shown to strongly bind large amounts of hexachlorophene.Fur- thermore, at low concentrations, hexachlorophene inhibited micro- somal 0-demethylase, nitroreductase, and glucuronide synthetase activities.Hexachlorophene also caused a decrease in microsomal cytochromes P-450 and b5 absorbancies, suggesting that interference with these microsomal components may be responsible for the ob- served in vitro inhibition of microsomal enzyme activity. Hexachlorophene: Its Absorption, Distribution, Excretion, and Biotransformation in the Rat and Rabbit and In Vitro Interaction with Rat Liver Microsomes by Allen Jay Gandolfi A THESIS submitted to Oregon State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy June 1973 APPROVED: Redacted for Privacy Associate Professor of Biochemistry in charge of major Redacted for Privacy Chairman of the Dpartment of Biochemistry Redacted for Privacy Dean of Graduate School Date thesis is presented 10 `-Z,,,61 A Typed by Cheryl E. Curb for Allen Jay Gandolfi DEDICATION To my Parents for their faith, love, and reassurance ACKNOWLEDGEMENTS I wish to express my sincere appreciation to Dr. D. R. Buhler for giving me the chance to study the biological side of chemistry and for his guidance and understanding throughout this work.Special thanks should go to Doctors R. E. Larson and D. J. Reed for their helpful suggestions and interesting discussions during my training. I am grateful to Dr. F. N. Dost for his advice and laboratory space during portions of this project and am indebted to Mr. D. A. Griffin for his operation of the Varian MATS spectrometer and to Miss M. E. Rasmusson for performing the tissue distribution analyses and for her expert management of the laboratory. Finally, I must thank my wife, Judith, and my sons, Christopher and Matthew, for their cheerful support throughout the successes and disappointments of my graduate training. Support for my graduate training came from a traineeship from the Environmental Health Sciences Center - PHS Grant P10-00210. Financial support for research came from USPHS and NIH Grants ES-00210 and FD-00041. TABLE OF CONTENTS Page INTRODUC TION 1 General 1 Chemistry of Hexachlorophene 3 Toxicology of Hexachlorophene 5 Absorption, Distribution, Biotransformation, and Excretion of Xenobiotics 8 Absorption, Distribution, Excretion, and Biotransformation of Phenolic Compounds 13 Absorption, Distribution, Excretion, and Biotransformation of Hexachlorophene 16 Purpose of the Study 21 MATERIALS AND METHODS 22 Materials 22 Preparation of Reference Compounds 24 Animals 27 Collection of Urine and Feces 28 Preparation of Rat Liver Microsomes 28 Radioactivity Counting Techniques 29 Extractions and Partition of Radioactivity 31 Extraction of Conjugates with Amber lite XAD-2 34 Thin Layer Chromatography 34 Adsorption Column Chromatography 37 Gas Chromatography 39 Preparation of Samples for Gas Chromatography 40 Mass Spectra 41 RESULTS. PART I: ABSORPTION, EXCRETION, AND BIOTRANSFORMATION OF HEXACHLOROPHENE IN THE RAT 45 Tritiation of Hexachlorophene 45 Isolation and Fractionation of Urine and Fecal Radioactivity 47 Analysis of Urine and Fecal Fractions 50 Analysis of Urine and Feces from Rats Receiving Repeated Doses of Non labeled Hexachlorophene 54 Analysis of Feces of Rats Fed Hexachlorophene in the Diet 56 Biliary Excretion of Hexachlorophene-14C Radio- activity 57 TABLE OF CONTENTS (Cont. ) Page Analysis of Biliary Radioactivity 60 DEAE-cellulose Chromatography of Bile Extract 62 Reabsorption of Biliary Hexachlorophene-MC Radioactivity 66 Ligation of the Bile Duct Prior to Hexachlorophene-14C Administration 70 RESULTS. PART II: ABSORPTION, DISTRIBUTION, BIOTRANSFORMATION, AND EXCRETION OF HEXACHLOROPHENE IN THE RAT 74 Absorption and Excretion 74 Tissue Distribution 77 Re spiration Studies 80 Isolation and Fractionation of Urine and Fecal Radioactivity 82 Analysis of the Urine Fractions 87 Analysis of the Fecal Fractions 93 Isolation and Identification of Hexachlorophene Glucuronide 99 RESULTS. PART III:IN VITRO INTERACTION OF HEXACHLOROPHENE WITH RAT LIVER MICROSOMES 108 Incubation of Hexachlorophene-MC with a Rat Liver Oxidative Microsomal Incubation System 108 Reaction of Hexachlorophene-14C with a Model Microsomal System 109 Attempts to Biosynthesize Hexachlorophene Glucuronide 109 Binding of Hexachlorophene-14C to Microsomes 111 Effect of Hexachlorophene on the Production of NADPH by Microsomal Incubation Mixtures 114 In Vitro Effect of Hexachlorophene on Microsomal Enzymatic Activity 116 In Vitro Effect of Hexachlorophene on Microsomal Components 120 DISCUSSION 128 BIBLIOGRAPHY 153 LIST OF FIGURES Figure Page 1 Hexachlorophene, HCP, G-11, 2, 2' -methylenebis- (3, 4, 6-trichlorophenol). 3 2 Methylene-14C-hexachlorophene. 5 3 Sites of biotransformation on phenols. 15 4 Excretion of radioactivity in the urine and feces of rats receiving 5 mg/kg ofhexachlorophene-14C orally or by intraperitoneal injection. 19 5 Stepwise fractionation of fecal extract, urine, or bile. 33 6 Separation of hexachlorophene, 2, 4, 5-trichlorophenol, and 3, 5-dichlorosalicylic acid by silicic acid column chromatography. 38 7 Characteristic m/e ion patterns of compounds containing six chlorines and three chlorines. 43 8 Mass spectrum of hexachlorophene. 44 9 Excretion of radioactivity in the bile of bile cannulated rats receiving intraperitoneal administration of 14C-hexachlorophene. 59 10 Chromatography of the Amberlite XAD-2 resin extract of bile from rats treated with hexachlorophene on DEAE - cellulose. 63 11 Replica of radiochromatograms from thin layer chromatographic analysis of enzyme hydrolyzed peak A aliquots (Figure 10). 64 12 Pattern of peak A parent ion. 65 13 Diagram of the surgical preparation of two rats to study biliary excretion and enterohepatic circulation. 67 14 Percent excretion of radioactive dose in the bile of rat B receiving bile from another rat A dosed intra- peritone ally with 5 mg/kg ofhexachlorophene-14C. 69 LIST OF FIGURES (Cont. ) Figure Page 15 Excretion of radioactivity in the urine and feces of a bile duct ligated rat receiving 5 mg/kg of hexachlorophene-14C intraperitoneally. 72 16 Excretion of radioactivity in the urine and feces of rabbits receiving a 10 mg/kg or 15 mg/kg intraperitoneal administration ofhexachlorophene-14C. 75 17 Excretion of conjugated and nonconjugated radioactive metabolites with respect to time in pooled urine from two rabbits receiving a 15 mg/kg intraperitoneal dose of hexachlorophene-14C. 83 18 Silicic acid column chromatography of one-fifth of the pooled concentrated rabbit urine fractions (Table 7) from rabbits receiving 15 mg/kg hexa- chlorophene-14C intraperitoneally. 90 19 Silicic acid column chromatography of 600 mg aliquot of concentrated fecal nonconjugated fraction (Table 8) from rabbits receiving 15 mg/kg hexa- chlorophene-14C intraperitoneally, 95 20 Silicic acid column chromatography of peak B from Figure 9 from fecal extract from rabbits receiving a 15 mg/kg intraperitoneal administration of hexachlorophene-14C. 97 21 Silicic acid column chromatography of major radio- active peak from florisil and alumina column chromatography of methylated and acetylated oil from pH 1 extract of urine from rabbits receiving hexachlorophene-14C. 109 22 2-(methyl 2, 3, 4-tri-0-acety1-(3-D-glucopyranuronate)- 2' -R-3, 3', 5, 5', 6, 6' -hexachlorodiphenylmethane. 105 23 Formation of monomethyl and monoacetyl hexachloro- phene-methyl acetoglucuronate during derivation of hexachlorophene monoglucuronide. 106 LIST OF FIGURES (Cont. ) Figure Page 24 Flow scheme of radioactivity in washed microsomes after isolation from a microsomal incubation mixture treated with hexachlorophene-14C. 112 25 Amount of hexachlorophene-14C bound to micro- somal membranes. 113 26 Production of NADPH by microsomal incubation mixtures in the presence
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