Zonation of hepatic cytochrome P-450 expression and regulation

Abstract

The CYP genes encode enzymes of the cytochrome P-450 superfamily. Cytochrome P-450 (CYP) enzymes are expressed mainly in the liver and are active in mono-oxygenation and hydroxylation of various xenobiotics, including drugs and alcohols, as well as that of endogenous compounds such as steroids, bile acids, prostaglandins, leukotrienes and biogenic amines. In the liver the CYP enzymes are constitutively expressed and commonly also induced by chemicals in a characteristic zonated pattern with high expression prevailing in the downstream perivenous region. In the present review we summarize recent studies, mainly based on rat liver, on the factors regulating this position-dependent expression and induction. Pituitary-dependent signals mediated by growth hormone and thyroid hormone seem to selectively down-regulate the upstream periportal expression of certain CYP forms. It is at present unknown to what extent other hormones that also affect total hepatic CYP activities, i.e. insulin, glucagon, glucocorticoids and gonadal hormones, act zone-specifically. The expression and induction of CYP enzymes in the perivenous region probably have important toxicological implications, since many CYP-activated chemicals cause cell injury primarily in this region of the liver.

Cytochrome P450 1A1 and aromatase (CYP19) in cetaceans : enzyme expression and relationship to contaminant exposure

“…1995Dey et al I999). The expression of CYPIA proteins in mamalian liver is typically zonal, highest expression is centrilobular and becomes panlobular with high induction (Oinonen and Lindros 1998;Drahushuk et al 1999). The same zonal pattern of CYPlAI expression has been seen in pilot whale liver (Stegeman et al I994).…”

“…Although some of the details, such as the number of AHRs present in a species (Hahn 2002), may var, the induction of CYPIAI by PAHs and PHAs through the AHR is well understood Vertebrates generally show high levels of CYPlAl induction in the liver. In mamals, hepatic CYPIAI has a zonal expression pattern in which panlobular expression of CYPlAl typically is seen only in highly induced organisms (Oinonen and Lindros 1998).…”

The Uptake Mechanism of Gallium-67 into Hepatocytes Treated with Carbon Tetrachloride

“…The uptake of 67 Ga by PVH treated with CCl 4 was also higher than that by PPH. These results showed that PVH preferentially suffered from cell damage because of high expression of CYP2E1 25,34) and 67 Ga was preferentially taken up into more damaged hepatocytes, PVH.…”

A 26-Week Carcinogenicity Study of 2-Amino-3-Methylimidazo[4,5-f]Quinoline in rasH2 Mice

“…Thus, there is a possibility that periportal hepatocyte hypertrophy is probably caused by the induction of enzyme. However, since the localization pattern of CYP 1A2 induction is not always specific to the periportal region (Oinonen and Lindros, 1998), further studies are required to clarify the causes of hepatocyte hypertrophy.…”