Date of Award:

5-1-1989

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Biology

Department name when degree awarded

Toxicology

Committee Chair(s)

Roger A. Coulombe, Jr.

Committee

Roger A. Coulombe, Jr.

Committee

William Brindley

Committee

Steven Oberg

Committee

Thomas Grover

Abstract

Aflatoxin B1 (AFB1) appears to be a risk factor in the development of tracheobronchial tumors in workers occupationally exposed to AFB1-laden dusts. Tracheal microsomal preparations and explant cultures from species rich (rabbit and hamster) and poor (rat) in numbers of metabolically active non-ciliated tracheal epithelial (NC) cells were used to study the possible effects of this mycotoxin in the upper airways. The metabolism of AFB1 and AFB1-DNA adduct formation was greatest in rabbit tracheal explants followed by the hamster with minimal AFB1 metabolism and AFB1-DNA binding in the rat. Novobiocin significantly inhibited adduct removal in hamster and rabbit tracheal explants demonstrating that removal of AFB1-DNA adducts is primarily an enzymatic process. Removal of AFB1-N7-Gua accounted for the majority of adduct disappearance. The AFB1-FAPyr adduct was the primary DNA lesion 84 hr post-treatment in all three species. The rabbit had the greatest cytosolic glutathione S-transferase activity and the highest tracheal microsomal pentoxyresorufin-0-dealkylase activity. Tracheal microsomal AFB1-diol production, cytochrome P-450 content, P-450 reductase, ethoxyresorufin-0-dealkylase and epoxide hydrolase activities were highest in the hamster. Aflatoxin B1 and several of its metabolites were released from polar aflatoxin conjugates after treatment of culture media with β-glucuronidase and arylsulfatase, demonstrating that the phase II conjugating enzymes UDP-glucuronsyl-transferase and sulfotransferases are present in the upper airways of mammals. The abilities of pulmonary S9 from these three species to activate AFB1 and benzo[a]pyrene (BP; a known respiratory carcinogen) to bacterial mutagens were also compared. In all cases, AFB1 produced more revertants per nanogram than did BP. Activation of AFB1 by tracheal S9 was greatest in rabbit followed by hamster then rat. These studies demonstrate that the metabolic capabilities of tracheal epithelium in these three species vary significantly. Hamster upper airways contain P-450 isozymes primarily involved in AFB1 detoxication, whereas isozymes involved in AFB1 activation predominate in rabbit tracheal epithelium. The overall metabolic activity in rat trachea is low. Furthermore, the presence of NC cells is a qualitative indicator of carcinogen metabolism in upper airways.

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