Metabolism of aflatoxin B{sub 1} in Turkey liver microsomes: The relative roles of cytochromes P450 1A5 and 3A37

Journal Article · Mon Aug 01 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.05.010· OSTI ID:21587800

Rawal, Sumit

The extreme sensitivity of turkeys to aflatoxin B{sub 1} (AFB{sub 1}) is associated with efficient epoxidation by hepatic cytochromes P450 (P450) 1A5 and 3A37 to exo-aflatoxin B{sub 1}-8,9-epoxide (exo-AFBO). The combined presence of 1A5 and 3A37, which obey different kinetic models, both of which metabolize AFB{sub 1} to the exo-AFBO and to detoxification products aflatoxin M{sub 1} (AFM{sub 1}) and aflatoxin Q{sub 1} (AFQ{sub 1}), respectively, complicates the kinetic analysis of AFB{sub 1} in turkey liver microsomes (TLMs). Antisera directed against 1A5 and 3A37, thereby individually removing the catalytic contribution of these enzymes, were used to identify the P450 responsible for epoxidating AFB{sub 1} in TLMs. In control TLMs, AFB{sub 1} was converted to exo-AFBO in addition to AFM{sub 1} and AFQ{sub 1} confirming the presence of functional 1A5 and 3A37. Pretreatment with anti-1A5 inhibited exo-AFBO formation, especially at low, submicromolar ({approx} 0.1 {mu}M), while anti-3A37, resulted in inhibition of exo-AFBO formation, but at higher (> 50 {mu}M) AFB{sub 1} concentrations. Metabolism in immunoinhibited TLMs resembled that of individual enzymes: 1A5 produced exo-AFBO and AFM{sub 1}, conforming to Michaelis-Menten, while 3A37 produced exo-AFBO and AFQ{sub 1} following the kinetic Hill equation. At 0.1 {mu}M AFB{sub 1}, close to concentrations in livers of exposed animals, 1A5 contributed to 98% of the total exo-AFBO formation. At this concentration, 1A5 accounted for a higher activation:detoxification (50:1, exo-AFBO: AFM{sub 1}) compared to 3A37 (0.15: 1, exo-AFBO: AFQ{sub 1}), suggesting that 1A5 is high, while 3A4 is the low affinity enzyme in turkey liver. The data support the conclusion that P450 1A5 is the dominant enzyme responsible for AFB{sub 1} bioactivation and metabolism at environmentally-relevant AFB{sub 1} concentrations in turkey liver. - Graphical abstract: Display Omitted Highlights: > Efficient bioactivation by P450s 1A5 and 3A4 associated with extreme aflatoxin B{sub 1} sensitivity in turkeys. > These P450s exhibit different metabolite profiles and enzyme kinetic models toward AFB{sub 1}. > Study conducted to determine which P450 is primary bioactivator in turkey liver. > Immunoinhibition studies show 1A5 predominates at low, environmentally-relevant AFB{sub 1} concentrations. > 3A37 predominates at only at very high AFB{sub 1} concentrations, not relevant to liver in vivo.

• OSTI ID: 21587800
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 254; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AFLATOXINS
ANIMALS
ANTIGENS
ASIA
BODY
CELL CONSTITUENTS
CONTROL
CYTOCHROMES
DETOXIFICATION
DEVELOPING COUNTRIES
DIFFERENTIAL EQUATIONS
DIGESTIVE SYSTEM
DRUGS
ENZYMES
EPOXIDES
EQUATIONS
GLANDS
GLUTATHIONE
GLUTATHIONE CONJUGATES
HAZARDOUS MATERIALS
HILL EQUATION
IN VIVO
LIVER
MATERIALS
METABOLISM
METABOLITES
MICROSOMES
MIDDLE EAST
MYCOTOXINS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PEPTIDES
PIGMENTS
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RIBOSOMES
SENSITIVITY
TOXIC MATERIALS
TOXINS
TURKEY