Ontogenetic development of the distribution of constitutive and 3-methylcholanthrene-induced CYP1A1 and CYP1A2 in rabbit liver.

Abstract

We investigated the expression, distribution, and inducibility of 3-methylcholanthrene (MC)-inducible P450 enzymes, CYPlAl and 1A2, in livers of rabbits at different stages of development, ranging from 4 days before birth (-4 days of age) to adulthood. These enzymes were identified by immunoblotting and immunocytochemistry and quantified by dot-blotting, utilizing previously characterized monoclonal antibodies, 107 and 31412, specific for CYPIA2 and both CYPlAl and 1A2, respectively, and a polydonal antibody that recognizes both enzymes. Expression of CYPIA2 is always greater than that of CYPlAl in livers of untreated rabbits, regardless of age. Moreover, immunocytochemistry showed that CYPlAl is evenly distributed throughout the liver at all ages, whereas CYPIA2 is highly localized to only a few scattered cells at 1 day before birth. More hepatocytes express this enzyme perinatally. By 6 days of age, expression of CYPIA2 is confined to a narrow band of centrilobular ceb, but with increasing age the enzyme is expressed in more hepatocytes until weaning, when all hepatocytes are posi-

Expression and inducibility of P450 enzymes during liver ontogeny

“…For example, PAHs differentially affect the levels of CYP1A1 and 1A2 in both rats Cresteil et al, 1986) and rabbits (Rich et al, 1993). In respective microsomal samples from 3-methylcholanthrene (MC)-treated rats, an immunoreactive band comigrating with 1A1 is evident at 24 hours pre-and postpartum, indicating transplacental induction of this enzyme (Fig.…”

“…In the rabbit, a weak immunoreactive band for CYP1A1 is detected in microsomal samples in livers of 6-day-old neonates, weanlings, and adults; none is detected between the ages of 9 and 21 days or prenatally. CYP1A2, in contrast, is detected in samples from rabbits of 6 days of age and older, the level of which increases with age (Rich et al, 1993). Constitutive levels of 1A1, as determined by dot blotting, represent Ͻ5% of total cytochrome P450, regardless of age (Table 2).…”

The Murine Cyp1a1 Gene Is Expressed in a Restricted Spatial and Temporal Pattern during Embryonic Development

“…CYP1A1 expression during embryonic development remains poorly characterized (7)(8)(9)(10). It has been suggested that CYP1A1 mRNAs have a short half-life that contributes to the difficulty in reliable detection (11).…”

Age-Specific Regulation of Drug-Processing Genes in Mouse Liver by Ligands of Xenobiotic-Sensing Transcription Factors

“…Previous studies have illustrated various inducibilities of drug-metabolizing enzymes during development in different species. For example, the hepatic Gst exhibited functional heterogeneity in mice, rats, rabbits, and guinea pigs after pretreatment with Gst inducers (Gregus et al, 1985); The ontogenetic expression and localization of Cyp1a1 and Cyp1a2 in the livers of rabbits are differently regulated with increasing age (Rich et al, 1993); More studies used the rat model to identify the activities of P450 after maximal induction, such as Cyp1a1/1a2 and Cyp2b1/2b2 by phenobarbital (Horbach et al, 1992;Agrawal and Shapiro, 1996), Cyp3a by dexamethasone (Lee and Werlin, 1995;Wauthier et al, 2004), or Cyp1a, Cyp2b, and Cyp3a induction by inducer dimethylcyclosiloxanes in fetal liver of rats (Falany and Li, 2005). However, most of these studies are limited to one category of drug-metabolizing enzymes in response to a single inducer.…”