The Regulation by Gender, Strain, Dose, and Feeding Status of the Induction of Multiple Forms of Cytochrome P450 Isozymes in Rat Hepatic Microsomes by 2,4,5,2′,4′,5′-Hexachlorobiphenyl

Stepping backward to improve assessment of PCB congener toxicities.

“…It is now known that 3-MC-TCDD-like induction increases aryl hydrocarbon hydrolase, CYPIAI, CYP1A2, and CYPIBI; PB-like induction increases CYP2B1, CYP2B2, CYP2A1, and CYP3A (2,4,7,13,17,22,38,(82)(83)(84)(85). A number of additional phase 1 and phase 2 enzymes, especially UDPGTs, are also induced in concert (85,86) or with separate SARs (4,7,31,34,(36)(37)(38)(87)(88)(89)(90)(91)(92).…”

“…PROD activity has been included in some surveys, but BROD appears to be a more sensitive indicator of exposure and may be more appropriate than PROD. Both basal activity and PCB inducibility is higher for BROD than for PROD in prepubertal rodents (17,37,38,43,71,85,87). Basal BROD activity is lower in adult female rats than in male rats and PCB induction of BROD activity in adult male Sprague-Dawley rats may be twice that of adult females (99).…”

“…Failure to discriminate between CYP2B and CYP3A activities with BROD as a substrate is not especially critical as CYP2A1, CYP2B1/2, and CYP3A are regulated in concert by an endocrine-sensitive process (85,86,105). As endocrine disruption is a major consideration in associating PCB actions with bioindicators, the more inclusive BROD would be preferred because all four of these monooxygenases are important in the catabolism of steroids, especially testosterone (85,86,91,96,97,105 (38,87,106).…”

“…A number of additional phase 1 and phase 2 enzymes, especially UDPGTs, are also induced in concert (85,86) or with separate SARs (4,7,31,34,(36)(37)(38)(87)(88)(89)(90)(91)(92). CYPs of the 4A family are induced or suppressed, depending on congener and species (89).…”

“…The selective O-dealkylation and O-dearylation of resorufin ethers offers a sensitive in vitro estimation of the selective induction of critical P450s (7,38,85,87,(93)(94)(95)(96) (96,98). An erythromycin breath test or urinary excretion of 6,B-hydroxycortisol are useful human biomarkers for CYP3A4 (91).…”