title: Frequency of urination and its effects on metabolism, pharmacokinetics, blood hemoglobin adduct formation, and liver and urinary bladder DNA adduct levels in beagle dogs given the carcinogen 4-aminobiphenyl.
abstract: The human urinary bladder carcinogen, 4-aminobiphenyl (ABP), is known to undergo hepatic metabolism to an N-hydroxy arylamine and its corresponding N-glucuronide. It has been proposed that these metabolites are both transported through the blood via renal filtration to the urinary bladder lumen where acidic pH can facilitate the hydrolysis of the N-glucuronide and enhance the conversion of N-hydroxy-4-aminobiphenyl (N-OH-ABP) to a reactive electrophile that will form covalent adducts with urothelial DNA. Blood ABP-hemoglobin adducts, which have been used to monitor human exposure to ABP, are believed to be formed by reactions within the erythrocyte involving N-OH-ABP that has entered the circulation from the liver or from reabsorption across the urothelium. To test these hypotheses directly, experimental data were obtained from female beagles given [3H]ABP (p.o., i.v., or intraurethrally). [3H]N-OH-ABP (i.v. or intraurethrally), or [3H]N-OH-ABP N-glucuronide (i.v.). Analyses included determinations of total ABP in whole blood and plasma, ABP-hemoglobin adducts in blood erythrocytes, ABP and N-OH-ABP levels (free and N-glucuronide) in urine, urine pH, frequency of urination (controlled by urethral catheter), rates of reabsorption of ABP and N-OH-ABP across the urothelium, and apparent volumes of distribution in the blood/tissue compartment. The major ABP-DNA adduct, N-(guan-8-yl)-4-aminobiphenyl, was also measured in urothelial and liver DNA using a sensitive immunochemical method. An analog/digital hybrid computer was then utilized to construct a multicompartmental pharmacokinetic model for ABP and its metabolites that separates: (a) absorption; (b) hepatic metabolism and distribution in blood and tissues; (c) ABP-hemoglobin adduct formation; (d) hydrolysis and reabsorption in the urinary bladder lumen; and (e) excretion. Using this model, cumulative exposure of the urothelium to free N-OH-ABP was simulated from the experimental data and used to predict ABP-DNA adduct formation in the urothelium. The results indicated that exposure to N-OH-ABP and subsequent ABP-DNA adduct formation are directly dependent on voiding frequency and to a lesser extent on urine pH. This was primarily due to the finding that, after p.o. dosing of ABP to dogs, the major portion of the total N-OH-ABP entering the bladder lumen was free N-OH-ABP (0.7% of the dose), with much lower amounts as the acid-labile N-glucuronide (0.3% of the dose).(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: National Center for Toxicological Research, Jefferson, Arkansas 72079.
authors.forename: F F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: K L
authors.initials: KL
authors.lastname: Dooley
authors.forename: C H
authors.initials: CH
authors.lastname: Teitel
authors.forename: D W
authors.initials: DW
authors.lastname: Roberts
authors.forename: R W
authors.initials: RW
authors.lastname: Benson
authors.forename: M A
authors.initials: MA
authors.lastname: Butler
authors.forename: J R
authors.initials: JR
authors.lastname: Bailey
authors.forename: J F
authors.initials: JF
authors.lastname: Young
authors.forename: P W
authors.initials: PW
authors.lastname: Skipper
authors.forename: S R
authors.initials: SR
authors.lastname: Tannenbaum
mesh_terms: D000611:Aminobiphenyl Compounds / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008954:Models, Biological; D013997:Time Factors; D014018:Tissue Distribution; D001743:Urinary Bladder / Q000378:metabolism*; D014554:Urination
chemical_list: D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D006454:Hemoglobins; C006757:4-biphenylamine; D004247:DNA