Multiple forms of inducible drug-metabolizing enzymes: A reasonable mechanism by which any organism can cope with adversity

Abstract

All organisms possess a number of genetically regulated mechanisms in order to cope with rapid adverse changes in the environment. The two systems which appear to respond to a seemingly endless array of chemical specificities are the immune response and the induction of drug-metabolizing enzymes. Similarities and differences between the immunoglobulin and the cytochrome P-450-mediated monooxygenase systems are described. DNA insertion sequences, plasmid "transposons," maize "controlling elements," gene duplication, intervening sequences, and high-frequency intergenic recombination are all discussed as possible methods by which organisms can "adapt" quickly to a new selective pressure. If the regulation of P-450 induction resembles in any way the other methods by which pro- and eukaryotes cope genetically with numerous forms of environmental adversity, therefore, it is very likely that mammalian tissues contain hundreds, if not thousands, of inducible forms of P-450.

Turnover of bacterial glutamine synthetase: oxidative inactivation precedes proteolysis.

“…These forms differ in their substrate specificity, although overlap is evident. Nebert has speculated that the diversity of P-450 forms might be as great as that of antibodies (35). If so, there might exist specific isozymes ofcytochrome P-450 with specificity for a particular protein.…”

Molecular cloning of hepatic 5‐aminolevulinate synthase

“…Moreover, the strategy of using this RNA fraction rather than total RNA was adopted in order to simplify the differential screening of the cDNA library. Since many drug-induced proteins are synthesised by membrane-bound ribosomes [21] we were able to circumvent the problem of detecting other drug-inducible cDNAs.…”

Isolation and characterization of a cloned DNA sequence associated with the murine Ah locus and a 3-methylcholanthrene-induced form of cytochrome P -450

“…Furthermore, nothing is known yet about the size of the structural gene for cytochrome P1450. Further characterization of the mouse cytochrome Pl-450 structural gene and the identification and characterization of other mouse cytochrome P-450 structural genes should provide valuable insight into the understanding of the genetic regulation of cytochrome P450 induction, the ultimate number of possible (basal and induced) forms of cytochrome P450 and their evolution (6), and potentially useful assays for genetic differences in individual risk of cancer, drug toxicity, and teratogenesis in humans (32,33).…”

“…Because of problems with detergent solubilization of microsomal membranes, the isolation of truly homogeneous forms of cytochrome P-450 has remained exceedingly difficult. Amino acid sequence determination has been attempted, but the data are highly variable and inconsistent among laboratories-even for the first 5 or 10 amino acids at the NH2 terminus (2)(3)(4)(5)(6). Studies of the nucleotide sequence not only will complement any protein sequence data but also should provide important insight into the understanding of induction of cytochrome P-450 (6).…”

“…7; reviewed in ref. 6). With the use of an antibody to cytochrome P1-450 (7), at least two mRNA species associated with aryl hydrocarbon hydroxylase induction have been shown to be greatly increased in 3-methylcholanthrene-treated "Ah-responsive" C57BL/6N (B6) inbred mice; these two mRNAs are either present in low concentration or absent in 3-methylcholanthrene-treated "Ah-nonresponsive" DBA/2N (D2) inbred mice and control untreated B6 and D2 mice (8).…”