Derecho a la salud y supervivencia de los infantes en aras del principio superior del

When cDNA and cloning techniques were introduced in the 1980s,

more new forms of cytochrome P450 were isolated. Each laboratory involved

in cytochrome P450 isolation began developing its own nomenclature

system according to electrophoretic mobility, substrate specificity or

maximal absorption wavelength making the situation very complex. There

were cases where an enzyme was designated several different names. The

fact that cytochrome P450s have a broad substrate specificity and catalyse

different reactions make the classical method of naming an enzyme

according to its function very difficult.

When amino acid sequence data was derived from DNA sequences,

it made possible a naming system based on the amino acid sequence

similarities. Table 1.2 lists a few examples of cytochrome P450s to illustrate

the diversity of the previous nomenclature and how the new classification

helped to overcome this complexity. Since it was first recommended in 1987

(Nebert, et al., 1987), there have been a few revisions (Nebert, at al., 1989,

Nebert, etal., 1991, Nelson, etal., 1993, Nelson, et al., 1996). A cytochrome

P450 gene is named by the italicised root symbol ‘CVP (‘Cyp’ for mouse

and Drosophila) to denote Cytochrome P450, followed by an Arabic number

for the family, a letter for the subfamily and another Arabic number for the

individual gene, i.e. CYP2B1 ÇCyp2bT in mouse). A pseudogene will have

a ‘P (‘ps’ in mouse and Drosophila) after the gene number. The non­

italicised form and all capital letters should be used for mRNA, cDNA and

Trivial name Rat

(name according to the laboratories of)

Gene Symbol Ryan Guengerich Waxman Rabbit Mouse Human CYP1A1 c pNF-B p-NF-B LM6 Pi450 _Pi

CYP1A2 d pNF/ISF-G ISF-G LM4 P3 4 5O _Pi

CYP2A1 a UT-F 3 - - -

CYP2B1 b PB-B PB-4 LM2 - -

CYP2B2 e PB-D PB-5 LM2 - -

CYP2C6 k PB-C PB-1 - - -

CYP2C11 h UT-A 2c - P450 16a -

CYP2C12 i UT-I 2d - P450 15P -

CYP2D1 - UT-H - - - dbi

CYP2E1 _j - - LM3a - j

CYP3A1 _P - - LM3 - P450nf

CYP4A1 - PB/PCN-E PB-2a - - -

Table 1.2 Diversity of nomenclature of some mammalian CYPs. (adapted from (Paine, 1991, Soucek and Gut, 1992) and references therein for sources of nomenclature)

1996). Members within the same family are defined as usually having >40%

amino acid sequence identity and mammalian sequences within the sam e

subfamily are always >55% identical. Although these definitions were made

arbitrarily, they turned out to be very useful despite a few exceptions

(reviewed in (Nelson, etal., 1993, Nelson, 1998)).

By 1996, 481 CYP genes were identified in 85 eukaryote and 20

prokaryote species, the number is still increasing (Nelson, at a!., 1996). But

how did CYP evolve to become such a superfamily of proteins? This

superfamily is ancient and believed to have begun with only a few genes

coding for CYP forms that were engaged in the metabolism of endogenous

substrates important for cellular functions (Nebert, 1991, Soucek and Gut,

1992). The increase in the number of CYP genes, according to the

evolutionary tree, arose during the past 400 million years. And ‘animal-plant

war-fare' is believed to be the driving force for the recent burst in new CYP

genes, particularly in the CYP2 family (Nebert and Gonzalez, 1987, Gonzalez

and Nebert, 1990). New genes encoding for new forms of CYP appear

through increased frequency of gene duplications and conversions as the

animal continues to encounter new types of foreign compounds, including

drugs and pesticides of the present days.

The diversity of genes has evolved mainly in the CYP families 1 to 4.

Hence, it is not surprising to find these four families more important in

xenobiotic metabolism than the other CYP families which are involved

mainly in the metabolism of endogenous substrates such as steroids, fatty

acids and hormones (Table 1.3). Apparently, most of the CYPs involved in

Gene families

Occurrence and functions

CYP1 Vertebrates; dioxin-induclbie; metabolism of polycyclic

hydrocarbon, halogenated and heterocyclic hydrocarbon, and aromatic amines

CYP2 Vertebrates and invertebrates; metabolism of drugs

and environmental chemicals

CYP3 Vertebrates; metabolism of drugs and environmental

chemicals

CYP4 Vertebrates, fatty acid hydroxylases; invertebrates,

unknown function(s)

CYP5 Vertebrates; thromboxane synthase

CYP6 Insects; metabolism of plant products and pesticides

CYP7A Vertebrates; cholesterol 7a-hydroxylase

CYP7B Vertebrates; unknown function(s)

CYP8 Vertebrates; prostacyclin synthase

CYP9 Insects

CYP10 Molluscs (mitochondrial enzyme)

CYP11 Vertebrates; cholesterol side-chain cleavage, steroid

1 1p-hydroxylase, and aldosterone synthase

(mitochondrial enzyme)

CYP12 Insects (mitochondrial enzyme)

CYP13 Nematodes

CYP14 Nematodes

CYP15 Insects

CYP16 Nematodes

CYP17 Vertebrates; steroid 17a-hydroxylase

CYP18 Insects

CYP19 Vertebrates; aromatization of androgens

CYP21 Vertebrates; steroid 21-hydroxylase

CYP24 Vertebrates; steroid 24-hydroxylase (mitochondrial enzyme)

CYP27 Vertebrates; steroid 27-hydroxylase (mitochondrial enzyme)

CYP51 Animals, filamentous fungi, yeast and plants; sterol biosynthesis

CYP52 Yeast; alkane hydroxylase

CYP53 to CYP62 Fungi

CYP71 to CYP92 Plants

CYP73 Plants, cinnamic acid hydroxylase

CYP101 to CYP118 Bacteria

Table 1.3 Overview of CVP familles and enzymes functions in various species, (reproduced from (Nelson, et al., 1996))

in xenobiotic metabolism exhibit broad and overlapping substrate

specificities allowing them to deal with a wide range of foreign compounds.