Ortiz de Montellano Paul R.(Ed.) Cytochrome P450. Structure, Mechanism, and Biochemistry

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Hormonal Regulation of Liver Cytochrome P450 Enzymes

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Human Cytochrome P450 Enzymes

R Peter Guengerich

Background and History of

Development of the Field

Much of P450 research has always been done

with the view of appUcation to humans, even

when done with experimental animals and

microorganisms. Research with the human P450s

has been done in several stages, and clinical phar-

macology has utilized the knowledge at each point

in its development.

Aside from in vivo experiments with drugs,

human P450 work in the late 1960s and 1970s was

done with tissue samples, primarily biopsies. Some

data on metabolic patterns and rates were col-

lected^. In the late 1970s, several groups began to

purify P450s from human liver microsomes. The

first purified proteins, selected because of their

abundance and ease of purification, were probably

what are recognized now as P450 3A and 2C sub-

family proteins^^. Efforts were shifted to purifying

individual P450s on the basis of catalytic activities

with the evidence that in some cases a single P450

could be identified in this way; for example, the

enzyme now known as P450 2D6 was found to be

under monogenic control^. The approach is techni-

cally demanding because of

the

need to do separa-

tions in the presence of detergents and then remove

them from individual chromatography fractions

prior to analysis of catal3^ic activity. Nevertheless,

human P450s lAl (ref [6]), 1A2 (ref [7]), 2A6

(ref [8]), 2C9 (ref [9]), 2D6 (refs [7], [10], [11]),

and 3A4 (ref [12]), were isolated in this general

manner. Another general approach that was used

was purification from tissue on the basis of

immunochemical cross-reactivity with animal

P450si3-i5.

With the development of recombinant DNA

technology, cDNAs for many of the human P450s

were cloned in the 1980s^^ In the late 1980s,

methods came into use for the heterologous

expression of P450s, first in mammalian and yeast

systems, and then in baculovirus and (by the mid-

1990s) in bacterial systems^^^^. In the late 1980s,

the nomenclature system developed by Nebert^^

was applied and allowed individual human and

other P450s to be discussed on the basis of their

sequences. (For a guide to some of the earlier

nomenclature, see ref [22].)

By the early 1990s, much of the interest in

P450 research had shifted to the human P450

enzymes because of the availability of systems for

handling these. In particular, studies in the areas

of drug metabolism and chemical toxicology/car-

cinogenesis were facilitated by the knowledge that

a relatively small number of the P450s account for

a large fraction of the metabolism of the drugs and

other chemicals of interest. In the pharmaceutical

industry, the roles of the major hepatic P450s are

extensively studied in developing predictions

F. Peter Guengerich • Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University

School of Medicine, 638 Robinson Research Building, Nashville, TN.

Cytochrome P450: Structure, Mechanism, and Biochemistry, 3e, edited by Paul R. Ortiz de Montellano

Kluwer Academic / Plenum Publishers, New

York,

2005.

377

378

F. Peter Guengerich

about bioavailability, drug-drug interactions, and

toxicity. Since the publication of the chapter on

human P450s in the last edition of this book^^,

apparently all of the remaining human P450 genes

have been identified, and the number (57) appears

to be complete because of more general knowl-

edge about the human genome (html://dmelson.

utmem.edu/CytochromeP450.html). Much of the

progress since 1995 has involved extrahepatic

P450s, many with roles in the processing of

"endobiotic" chemicals, for example, sterols and

vitamins.

The list of the 57 human P450s is presented in

Table 10.1, along with available knowledge about

Table 10.1. Human P450s

P450

Tissue sites

Subcellular

localization'^

Typical reaction^

lAl

1A2

IBl

2A6

2A7

2A13

Lung, several

extrahepatic sites,

peripheral blood cells

Liver

Many extrahepatic

sites,

including lung

and kidney

Liver, lung,

and

several extrahepatic sites

Nasal tissue

2B6

2C8

2C9

2C18

2C19

2D6

2E1

2F1

2J2

2R1

2S1

2U1

2W1

3A4

3A5

3A7

3A43

4A11

4A22

4B1

4F2

4F3

4F8

Liver, lung

Liver

Liver, lung, other

tissues

Lung

Liver, small intestine

Liver, lung

Fetal liver

(mRNA detected

gonads)

Liver

Lung

Liver

Neutrophils

Seminal vesicles

ER^

(ER)

Benzo[a]pyrene

3-hydroxylation

Caffeine TV^-demethylation

17(3-Estradiol 4-hydroxylation

Coumarin

7-hydroxylation

Activation

4-(methylnitrosamino)-1

(3-pyridyl)-1

-butanone

(NNK)

(iS)-Mephenytoin A^-demethylation

Taxol 6a-hydroxylation

Tobutamine methyl hydroxylation

(5)-Mephenytoin 4'-hydroxylation

Debrisoquine 4-hydroxylation

Chlorzoxazone

6-hydroxylation

3-Methylindole

activation

Arachidonic acid oxidations

Testosterone 6p-hydroxylation

Testosterone

p-hydroxylation

Testosterone

p-hydroxylation

Fatty acid w-hydroxylation

Laurie acid w-hydroxylation

Leukotriene B^ w-hydroxylation

Prostaglandin a)-2 hydroxylation

Human P450s

379

Table 10.1. Continued

P450

4F11

4F12

4F22

4V2

4X1

4Z1

5A1

7A1

7B1

8A1

8B1

llAl

llBl

11B2

17A1

19A1

20A1

21A2

24A1

26A1

26B1

26C1

27A1

27B1

27C1

39A1

46A1

51A1

Tissue sites

Liver

Platelets

Liver

Brain

Aorta, others

Liver

Adrenals, other

steroidogenic tissues

Adrenals

Steroidogenic tissues

Steroidogenic tissues,

adipose, brain

Steroidogenic tissues

Kidney

Several

Brain

Liver

Kidney

Liver (?)

Brain

Liver, testes

Subcellular

localization"

Mit

(ER?)

Mit

Typical reaction*

Arachidonic acid ci)-,a)-2-hydroxylation

Thromboxane A^ synthase reaction

Cholesterol 7a-hydroxylation

Dehydroepiandrosterone

7a-hydroxylation

Prostacyclin synthase reaction

7a-hydroxyprogesterone

12-hydroxylation (?)

Cholesterol side-chain

cleavage

11-Deoxycortisol 11-hydroxylation

Corticosterone 18-hydroxy lation

Steroid 17a-hydroxylation

Androgen aromatization

17-Hydroxyprogesterone

21-hydroxylation

25-Hydroxyvitamin D3 24-hydroxylation

Retinoic acid 4-hydroxylation

Sterol 27-hydroxylation

Vitamin D3

1-hydroxylation

24-Hydroxycholesterol

7-hydroxylase

Cholesterol 24-hydroxylation (?)

Lanosterol 14a-demethylation

^ER = endoplasmic reticulum (microsomal), Mit = mitochondria.

^If known.

•^Mainly ER, some detected in mitochondria.

sites of tissue expression, subcellular localization,

and a typical reaction. In the 1995 edition^^, the

list included

human P450s, and 2 of these have

been dropped as apparent cloning artifacts (2C10,

2C17),

leaving 29. Thus, the list was only half

complete at that time. It should be emphasized

that we still have little knowledge about the roles

of some of these P450s beyond the genomic infor-

mation. Of the 57, most that have been examined

appear to be expressed primarily in the endoplas-

mic reticulum and only 6 are located exclusively

in mitochondria. (However, work in animal mod-

els by Avadhani has clearly demonstrated the

import of what have been generally considered

microsomal P450s into mitochondria^"^' ^^. The

basis of this transport appears to be signals in the

N-terminal region^^. Limited information is avail-

able about this phenomenon with human P450s;

380

F. Peter Guengerich

recent collaborative experiments with Avadhani's

group indicate that many human liver samples

contain immunochemically detectable and catalyt-

ically active P450 2D6 in mitochondrial as well

as microsomal fractions pST. Avadhani and

RR Guengerich, unpublished results].) In many

cases,

no direct information is available because

protein studies have not been done, although most

of these "orphan" P450s are predicted to reside

primarily in the endoplasmic reticulum.

Of the P450s with known catalytic activities, 14

are clearly involved in steroidogenesis, 4 are

involved in what appear to be important aspects of

metabolism of vitamins (vitamins A and D), 5 are

involved in eicosanoid metabolism, 4 appear to have

fatty acids as their substrates, and 15 catalyze trans-

formation of xenobiotic chemicals (Table 10.2).

Some of these categories should be considered ten-

tative. This classification accounts for only 42 of the

57 P450s. Many of the xenobiotic-metabolizing

P450s can also catalyze oxidation of steroids and

fatty acids, but these functions do not appear to be

critical to homeostasis (e.g., testosterone 6p-hydro-

xylation by P450 3A4, lauric acid 11-hydroxylation

by P450 2E1, possibly 17p-estradiol 4-hydroxyla-

tion by P450 IBl). Most of the steroid-oxidizing

enzymes are critical, and the levels of these P450s

are relatively invariable among individuals, in con-

trast to the xenobiotic-metabolizing P450s, which

vary considerably (Figures 10.1 and 10.2).

Deficiencies in the expression or catalytic activities

of most of the P450s involved in steroid metabohsm

lead to serious diseases (Table 10.3) (included in

this hst^^ are P450s IBl [true function unknown]

and 24A1 [vitamin D hydroxylation]). In one case,

a high level of P450 activity (P450 19) can be a

problem (estrogen formation in estrogen-dependent

tumors) and this P450 is a target for therapeutic

attenuation^^. The 15 identified xenobiotic-metabo-

lizing P450 are mainly in the families 1-3, and lev-

els of these vary considerably in humans (Figures

10.1 and 10.2). Studies with transgenic (knockout)

mice do not indicate critical function associated

with the apparent orthologs in the absence of

xeno-

biotic challenge^ ^ Analysis of the lists of drugs in

which individual human P450s are involved^^ indi-

cates that —75% of the drugs can be oxidized by

3 P450s (3A4, 2D6, 2C9), and a set of 6-7 P450s

will account for 90-95% of all drug metabolism

(Figure 10.3)^^. Similar numbers of P450s are

involved in the metabolism of chemical carcino-

gens,

although the pattern shifts from that of Figure

10.3,

with P450s 2C19 and 2D6 being replaced by

P450S lAl, IBl, 2A6, and 2E1 (Table 10.4). The

relative contributions of these xenobiotic-metaboliz-

ing P450s are, to some extent, a function of the rel-

ative abundance (Table 10.5, Figure 10.4), although

there are some important exceptions. Further, the

Table 10.2. Classification of Human P450s based on Major Substrate Class""

Sterols

IBl

7A1

7B1

8B1

llAl

llBl

11B2

21A2

27 A1

Xenobiotics

lAl

1A2

2A6

2A13

2B6

2C8

2C9

2C18

2C19

2D6

2E1

2F1

3A4

3A5

3A7

Fatty acids

2J2

4A11

4B1

4F12

Eicosanoids

4F2

4F3

4F8

5A1

8A1

Vitamins

26A1

26B1

27B1

Unknown

2A7

2R1

2S1

2U1

2W1

3A43

4A22

4F11

4F22

4V2

4X1

4Z1

26C1

27C1

''As pointed out in the text, this classification is somewhat arbitrary, for example, P450s IBl and 27A1

could be grouped in two different categories.

Human P450s

381

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Human P450s 383

Table 10.3. Diseases Associated with Mutations in CYP Genes^^

Gene Disorder

CYPIBI

CYP4A,

4B^

CYP5A1,

8A1

CYP7A1

CYP7B1

CYPUAl

CYPllBl

CYP11B2

CYPllBl, 11B2

CYPUAl

CYP19A1

CYP21A2

CYP24A1^

CYP27A1

CYP27B1

Primary congenital glaucoma (buphthalmos)

Defects in salt metabolism, water balance leading to arterial hypertension

Defects leading to clotting and inflammatory disorders, coronary artery disease, and

pulmonary hypertension

Hypercholesterolemia, resistance to statin drugs

Severe hyperoxysterolemia and neonatal liver disease

Lipoid adrenal hyperplasia; occasional congenital adrenal hyperplasia (CAH)

Occasional CAH

Corticosterone methyloxidase deficiency type I, or type II; occasional CAH

Chimeric enzymes causing glucocorticoid-remediable aldosteronism; occasional CAH

Mineralocorticoid excess syndromes, glucocorticoid, and sex hormone deficiencies;

association with increased risk of prostate cancer and benign prostatic hypertrophy;

occasional CAH

Loss of function: virilization of females, hypervirilization of

males,

occasional CAH; gain

of function: gynecomastia in young males

>90%ofallCAH

Hypervitaminosis D

Cerebrotendinous xanthomatosis

Vitamin D-dependent rickets type I

''Strong evidence of disease in animal models but not yet in clinical studies.

1A1

2C19

Figure 10.3. Estimated contributions of individual

human P450s to the metabolism of all drugs, based upon

literature available (adapted from Evans and Relling)^^.

patterns reported for human liver (Table 10.5,

Figures 10.1, 10.2, and 10.4) do not necessarily

apply in other

tissues,

some of which may be targets

for carcinogens and other toxicants^^.

General Issues of Variability

and Polymorphism

Variability in patterns of drug metabolism has

been recognized for some time, even before the

discovery of P450s. For instance, the phenomenon

of pharmacogenetic variation had been identified

by the

1950s^^'

and the early work of Remmer"^^

showed the influence of barbiturates upon drug

metabolism. Further, a number of congenital

defects in steroid metabolism were known and

some could be attributed to alterations in specific

hydroxylations'*^ Much of the subsequent work

on inducibility has been done in experimental ani-

mal models"^^ and later, cell culture.

In the 1960s and 1970s, a number of accounts

appeared describing variations in rates of metabo-

lism of drugs in human liver biopsy samples^ The

first characterization of a monogenic variability in

a human drug-metabolizing P450 was the work of

Smith with debrisoquine^, which was paralleled

by the work of Dengler and Eichelbaum on

sparteine"*^.

This polymorphism was first described

in the context of extensive metabolizers (EMs) and

poor metabolizers (PMs) (Figure 10.5). These

384

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