Down-regulation of multiple cytochrome p450 gene products by inflammatory mediators in vivo

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

“…Stanley et al (6) observed differential inhibition of P450 isozyme expression in rats with low doses of LPS, whereas high doses of LPS depressed all isoenzymes studied. Morgan (8) recently reported decreased P450 2C6, 2C7, 2Cl 1, 2C12, and 2E1 mRNA but decreased proteins for only P450 2C11, 2C12, and 2E1 after LPS administration. Since P450 isoenzymes vary between species, how these studies apply to humans is not clear.…”

“…Based on animal studies (8)(9)(10)(11)(12)(13)(14)(15), it is likely that depression of cytochrome P450-mediated drug metabolism after LPS is mediated by inflammatory cytokines, since administration of cytokines in these studies reproduced the depressions seen with LPS (8)(9)(10)(11)(12)(13)(14)(15). Supporting this contention is our finding that the decreases in AP clearance in EXP 2 correlated with peak TNF and IL-6 responses after the first dose of LPS (Fig.…”

Role of the aromatic hydrocarbon receptor in the suppression of cytochrome P-450 2C11 by polycyclic aromatic hydrocarbons

“…The differences in timecourse may be due to differences in the half-lives of the relevant mRNAs andor proteins (Hargrove and Schmidt, 1989), and it is clear that parallel dose-response curves for different biological responses can be separated by as much as several orders of magnitude and still be mediated by the same receptor (Okey et al, 1995). It is important to point out that a rat liver cytosolic 4 S carcinogen-binding protein may also be involved in the transcriptional induction of CYPl A I expression in response to nonhalogenated aromatic hydrocarbons (Houser et al, 1985 LeBlanc and Waxrnan, 1990) and cytokines and inflammatory mediators (Morgan, 1989;Morgan. 1993;Chen et al, 1995b) being the best characterized negative regulators.…”

Suppressive Effect of Polysaccharides from the Edible and Medicinal Mushrooms,Lentinus edodesandAgaricus blazei, on the Expression of Cytochrome P450s in Mice

“…5,6) Numerous studies have demonstrated that cytokines, including tumor necrosis factor (TNF)-a are involved in hepatic in‰ammation induced by such infectious stimuli as lipopolysaccharide (LPS). 7) In‰ammatory signaling down-regulates the expression of cytochrome P450s (CYPs), a class of drug-and xenobiotic-metabolizing enzymes mainly expressed in the liver, 8) and the suppression of CYP activity is considered to prolong the duration and intensify the action of a drug. 9) Moreover, this action contributes to the prevention of carcinogenesis, because the CYP1A subfamily, which is induced by xenobiotics such as polyaromatic hydrocarbons, metabolically activates procarcinogens.…”