The metabolism of 4-aminobiphenyl in rat. II. Reaction of N-hydroxy-4-aminobiphenyl with rat blood in vitro.
1. N-Hydroxy-4-aminobiphenyl (N-hydroxy-ABP) reacts with HbFe2+ of rat blood in vitro at a molar ratio of 1:47 to produce 20% HbFe3+ within 1 min; N-hydroxy-ABP oxidized 9.4 equiv. of HbFe2+. N-hydroxy-ABP rapidly disappeared and HbFe3+ was reduced at a rate of 44 microM/min. 2. On titration of rat blood in vitro with N-hydroxy-ABP up to 0.81 mM, 4-nitrosobiphenyl (nitroso-BP) disappeared within 5 min; with concn of N-hydroxy-ABP greater than 0.81 mM, N-hydroxy-ABP was present also as nitroso-BP, indicating saturation of reactive binding sites. When N-hydroxy-ABP reacted with HbFe2+ at a molar ratio of 1:103 to 1:1.9, 13 to 1.3 equiv. of HbFe3+ were formed per mol of N-hydroxy-ABP in 5 min, indicating that with increasing N-hydroxy-ABP concn side-reactions increased. 3. After incubation of N-hydroxy-ABP (1.72 mM) with rat Hb (7.66 mM HbFe2+), nitroso-BP disappeared with a half-life of 1 min, maximal HbFe3+ of 72% occurred at 47 min, and the concn of 4-aminobiphenyl (ABP) increased at a rate of 51 nmol/ml per h. 4. In rats injected with 0.24 mmol/kg ABP, HbFe3+ concn plateaued at 56% after 75 min, indicating an equilibrium between HbFe3+ formation and HbFe3+ reduction. Such equilibrium was simulated by titrating rat blood in vitro with N-hydroxy-ABP for 1 h. 5. The long-lasting HbFe3+ formation by ABP in rat results from a cycle of activation of ABP to N-hydroxy-ABP, its rapid co-oxidation with HbFe2+ to form HbFe3+ and nitroso-BP, and binding of nitroso-BP to erythrocyte thiol groups. ABP is released from the Hb adduct and enters a new cycle of activation and inactivation, until terminated by ring-hydroxylation.
Heilmair
R
R
Walther Straub-Institut für Pharmakologie und Toxikologie der LM-Universität, München, Germany.
Karreth
S
S
Lenk
W
W
D000611:Aminobiphenyl Compounds / Q000097:blood*; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D006454:Hemoglobins; C006757:4-biphenylamine; D010100:Oxygen