Comparison of major B[a]p responses in vitro and in vivo
Responses are summarized from a number of references (Robinson et al., 1975; Nebert and Jensen, 1979; Conney, 1982; Nebert, 1989; Whitlock, 1999; Uno et al., 2004, 2006).
Molecular Events | End Responses | |
|---|---|---|
| In vitro | Binding to AhR | ↑ Mutation in Ames test |
| Induction of CYP1A1 | ↑ Micronuclei formation in V79 cells | |
| Metabolic activation of B[a]p | ↑ Apoptosis and cell death of cultured cells | |
| ↑ trans-7,8-Diol 9,10 epoxide | Identification of genetic B[a]p-resistant variants | |
| ↑ DNA & protein adduct formation | ||
| In vivoa | ||
| Ah responsive (b/b or b/d) | Strong induction of CYP1A1 & metabolism at site of entry | Tumors and toxicity at proximate tissues Survival for >6 month |
| ↑ First-pass detoxification | ||
| Ah nonresponsive (d/d) | Weak metabolism at site of entry | Profound toxicity at distal tissues: bone marrow depression, leukocytopenia, & wasting |
| ↓ First-pass detoxification | ||
| Death within 30 days | ||
| ↑ Incidences of leukemia and thymomas at lower dose of B[a]p (12.5 mg/kg/day) | ||
| cyp1a1-/- | Similar to d/d | Profound toxicity and death similar to d/d |
↵ a Represents experiments in which B[a]p was given in corn oil-soaked food at daily oral B[a]p dose of ∼125 mg/kg/day for most responses or ∼12.5 mg/kg for tumor formation.