@article {GURTOO296, author = {HIRA L. GURTOO}, title = {Genetic Expression of Aflatoxin B1 Metabolism: Effects of 3-Methylcholanthrene and 2,3,7 ,8,-Tetrachlorodibenzo-p-dioxin on the Metabolism of Aflatoxins B1 and B2 by Various Inbred Strains of Mice}, volume = {18}, number = {2}, pages = {296--303}, year = {1980}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Hepatic microsomal metabolism of aflatoxin B1 to aflatoxins M1 (aflatoxin B1-4-hydroxylase), Q1 (aflatoxin B1-9-hydroxylase) and to B1-2,3-oxide (aflatoxin B1-2,3-oxygenase) and of aflatoxin B2 to aflatoxin M2 (aflatoxin B2-4-hydroxylase) was studied in inbred strains of mice pretreated with phenobarbital (PB), 3-methylcholanthrene (MC), or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In all strains tested (C57BL/6 Jacobs, BALB/cCr, CBA/J, C57L/J, DBA/2HaD, AKR/Sn, RF/J, and 129/J), PB induced aflatoxin B1-2,3-oxygenase (2.4- to 6.4-fold) and, with the exception of C57L/J, aflatoxin B1-9-hydroxylase (1.8- to 4.6-fold), whereas PB either had no effect or slightly induced aflatoxin in B1-4-hydroxylase. In comparison to this, MC either had no effect or caused depression of aflatoxin B1-2,3-oxygenase and of aflatoxin B1-9-hydroxylase activities. On the other hand, MC induced aflatoxin B1-4-hydroxylase (2.5- to 3.6-fold) and also aflatoxin B2-4-hydroxylase (3.1- to 4.8-fold) only in Ah responsive strains and not in Ah nonresponsive strains. Dose-response studies with TCDD indicated that both aflatoxin B1-4-hydroxylase and aflatoxin B2-4-hydroxylase are induced by TCDD in the Ah nonresponsive strain (DBA/2) provided a dose 9-fold higher than that used for the Ah responsive strain (C57BL/6) is administered. The ED50 value for aflatoxin B1-4-hydroxylase and aflatoxin B2-4-hydroxylase induction in DBA/2 strain (1.3 {\textmu}g/kg) was accordingly 9-fold higher than that in C57BL/6 (0.14 {\textmu}g/kg). In contrast, TCDD dose-response curves for aflatoxin B1-2,3-oxygenase and aflatoxin-9-hydroxylase were essentially similar in both strains, i.e., DBA/2 and C57BL/6. At the lowest dose, both activities increased slightly but as the dose increased, the activities either were inhibited or remained unaffected. The data indicate that (a) several cytochrome P-450s of the mixed function oxygenase participate in the metabolism of aflatoxin B1 via various pathways, (b) these pathways of aflatoxin B1 metabolism are under different regulatory controls, (c) the regulation of aflatoxin B1-4-/B2-4-hydroxylase and aryl hydrocarbon hydroxylase induction is controlled by the same or closely linked genetic factors at the regulatory gene level and not at the structural gene level, and (d) the regulation in (c) is most likely mediated by an induction-specific receptor which apparently has lower affinity for the inducer in the nonresponsive strain DBA/2. ACKNOWLEDGMENTS The author wishes to acknowledge the technical assistance provided by Ms. Lurine Hauser and also wishes to thank Ms. Karen Schrader and Ms. Sandi Randazzo for the assistance provided in the preparation of this manuscript.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/18/2/296}, eprint = {https://molpharm.aspetjournals.org/content/18/2/296.full.pdf}, journal = {Molecular Pharmacology} }