Hepatic and renal cytochrome p450 gene regulation during citrobacter rodentium infection in wild-type and toll-like receptor 4 mutant mice.

Citrobacter rodentium is the rodent equivalent of human enteropathogenic Escherichia coli infection. This study investigated regulation of hepatic and renal cytochrome P450 (P450) mRNAs, hepatic P450 proteins, cytokines, and acute phase proteins during C. rodentium infection. Female C3H/HeOuJ (HeOu) and C3H/HeJ (HeJ) mice [which lack functional toll-like receptor 4 (TLR4)] were infected with C. rodentium by oral gavage and sacrificed 6 days later. Hepatic CYP4A10 and 4A14 mRNAs were decreased in HeOu mice (<4% of control). CYP3A11, 2C29, 4F14, and 4F15 mRNAs were reduced to 16 to 55% of control levels, whereas CYP2A5, 4F16, and 4F18 mRNAs were induced (180, 190, and 600% of control, respectively). The pattern of P450 regulation in HeJ mice was similar to that in HeOu mice for most P450s, with the exception of the TLR4 dependence of CYP4F15. Hepatic CYP2C, 3A, and 4A proteins in both groups were decreased, whereas CYP2E protein was not. Renal CYP4A10 and 4A14 mRNAs were significantly down-regulated in HeOu mice, whereas other P450s were unaffected. Most renal P450 mRNAs in infected HeJ mice were increased, notably CYP4A10, 4A14, 4F18, 2A5, and 3A13. Hepatic levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNFalpha) mRNAs were significantly increased in infected HeOu mice, whereas only TNFalpha mRNA was significantly increased in HeJ mice. Hepatic alpha1-acid glycoprotein was induced in both groups, whereas alpha-fibrinogen and angiotensinogen were unchanged. These data indicate that hepatic inflammation induced by C. rodentium infection is mainly TLR4-independent and suggest that hepatic P450 down-regulation in this model may be cytokine-mediated.

Editorial: Take Me Home, Down Country Roads

Those of us committed to the tenets of Family Preservation must advocate for increased awareness and attention to the needs of children and their families in rural America. "Country roads" and the rural spaces they traverse have been eulogized by many poets and song writers as ideal places to live. But they may not be ideal for everyone. The past few months, it has become all too evident that rural America is not immune to acts of extreme violence by troubled children. Even though almost 1/3 of American youth live in rural areas, they have been "virtually ignored by mental health service planners and providers"(Cutrona, Halvorson, & Russell, 1996, p. 217). Mental health risk factors such as poverty, parental alcohol abuse, and family instability are on the rise in rural areas, and there has been an increase in suicide attempts, family violence, depression, and alcohol abuse (Cutrona, Halvorson, & Russell, 1996; Petti & Leviton, 1986; National Mental Health Association, 1988). Native Americans are especially concerned about the increases in child abuse and neglect, depression, substance abuse, and suicide in their communities.